Moderate-Penetrance Genes in Hereditary Breast Cancer and Non-BRCA Hereditary Ovarian Cancer

Literature and regulatory information updated: 4 October 2026.

CHEK2, PALB2, ATM, BARD1, RAD51C, RAD51D, BRIP1 and mismatch repair (MMR) genes: gene-specific risks, surveillance, risk-reducing surgery and multifactorial risk estimation (PRS/CanRisk)

0. Initial Reference Table

1. Introduction

Identification of BRCA1 and BRCA2 in the 1990s explained most families with clustering of early-onset breast and ovarian cancer, but it soon became clear that high-penetrance Mendelian genes account for only approximately 20% of relative familial breast cancer risk, with the remainder distributed across moderate-risk genes, hundreds of small-effect common variants and environmental factors [21]. For epithelial ovarian cancer, BRCA1, BRCA2 and MMR genes (MLH1, MSH2, MSH6) explain nearly half the excess familial risk, and subsequent research added BRIP1, RAD51C and RAD51D as susceptibility genes [22].

The “moderate-penetrance gene” concept arose from population genetics and case–control studies. In 2002, Meijers-Heijboer and colleagues demonstrated that truncating CHEK2 NM_007194.4:c.1100del p.(Thr367MetfsTer15) (historical designation c.1100delC), present in 1.1% of healthy individuals and 5.1% of breast cancer patients from 718 families without BRCA1/2 variants, approximately doubled female breast cancer risk and increased male risk tenfold, without adding risk in BRCA1/2 carriers — placing CHEK2 in the same biological pathway as BRCA proteins [23]. In 2006, Renwick and colleagues showed that ATM variants causing biallelic ataxia-telangiectasia are heterozygous breast cancer susceptibility alleles, with relative risk 2.37 (95% CI 1.51–3.78) [24]. That year, Seal and colleagues described truncating BRIP1 variants (the Fanconi anaemia group J gene) in breast cancer families, with estimated relative risk 2.0 [25]; in 2007, Rahman and colleagues identified monoallelic truncating PALB2 variants in 10 of 923 familial cases and none of 1084 controls, with initial relative risk 2.3 [26]. BARD1 had been identified in 1996 as a BRCA1 partner through RING domains [27].

The ovarian aspect consolidated between 2010 and 2011. Meindl and colleagues found six monoallelic pathogenic RAD51C variants in 1100 German families with gynaecological malignancies, all in breast–ovarian cancer lineages and none in breast-only families or 2912 controls [28]. Loveday and colleagues described eight inactivating RAD51D variants in 911 breast–ovarian families (ovarian cancer relative risk 6.30), associated mainly with ovarian rather than breast cancer, and demonstrated sensitivity of RAD51D-deficient cells to PARP inhibitors [29]. Rafnar and colleagues identified BRIP1 c.2040_2041insTT through Icelandic genomic sequencing, with ovarian cancer odds ratio (OR) 8.13 [30]. Initial BRIP1 breast risk estimates were not confirmed in larger subsequent studies, and BRIP1, RAD51C and RAD51D became considered moderate ovarian risk genes [21].

The current landscape rests on two case–control studies published in 2021 — that of the Breast Cancer Association Consortium (BCAC, BRIDGES project), with 60,466 cases and 53,461 controls, and that of the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, with 32,247 cases and 32,544 population-based controls — which defined which panel genes have clinical utility for breast cancer risk prediction [31, 32], and on family segregation studies that estimated age-specific absolute risks for PALB2, RAD51C and RAD51D [33, 34]. These data informed the practice resources of the American College of Medical Genetics and Genomics (ACMG), the British consensus of the UK Cancer Genetics Group (UKCGG) and the NCCN guidelines, and were incorporated into the CanRisk model, which allows the generic per-gene estimate to be replaced by an individual estimate combining genotype with family history, PRS and non-genetic factors [10–14, 18]. These entities complement hereditary breast and ovarian cancer predisposition syndrome due to BRCA1/2, with which PALB2 shares its epidemiological basis, and Lynch syndrome.

2. Molecular Genetics and Pathophysiology

2.1 The DNA damage response and homologous recombination pathway

These genes encode components of double-strand break damage signalling and homologous recombination repair (HRR, homologous recombination repair), the highest-fidelity repair mechanism for these breaks; functional defects are termed homologous recombination deficiency (HRD) [35]. Hierarchically, ATM is the principal sensor kinase: with a double-strand break (for example, after ionising radiation), it phosphorylates hundreds of repair, cell-cycle checkpoint and apoptosis proteins, including p53, CHK2 and BRCA1 [4]. CHK2, encoded by CHEK2, is an effector kinase of the ATM–CHK2–p53 pathway: recruited to damage by its FHA (forkhead-associated) domain, it phosphorylates CDC25A/B/C to arrest the cycle, BRCA2 and FOXM1 to promote recombination, and TP53, MDM4 and PML to trigger apoptosis [3, 5]. PALB2 (partner and localizer of BRCA2) links the BRCA1–PALB2–BRCA2 complex: it recruits BRCA2 and RAD51 to the break and stabilises the RAD51 nucleoprotein filament [5]. BARD1 forms a BRCA1 heterodimer with E3 ubiquitin ligase activity, whose integrity is necessary for BRCA1 tumour suppression [5, 27]. RAD51C and RAD51D are RAD51 paralogues in the BCDX2 complex (RAD51B–RAD51C–RAD51D–XRCC2), acting after BRCA2 recruitment and before RAD51 loading; RAD51C also forms part of the CX3 complex involved in branch migration and Holliday junction resolution [5]. BRIP1 (also FANCJ or BACH1) is an ATP-dependent 5'→3' helicase acting in the Fanconi pathway downstream of FANCD2 monoubiquitination and cooperating with BRCA1 in homologous recombination [5].

2.2 Disease mechanism and gene-specific tumour signature

The mechanism is loss of function, with tumour wild-type allele inactivation varying by gene, explaining a central clinical distinction: not all pathway genes produce HRD tumours. CHEK2-associated breast tumours typically lack genomic HRD features, unlike BRCA1, BRCA2 and PALB2 tumours [3, 11]. In ATM heterozygote breast cancers, nearly 80% show wild-type allele loss of heterozygosity, but none of 24 studied tumours had appreciable homologous recombination defects; genomic instability scores are also low in ATM-associated pancreatic adenocarcinoma, and prostate cancer HRD scores significantly lower than with BRCA2 [4]. Conversely, triple-negative tumours with RAD51C and RAD51D variants often show biallelic inactivation and functional HRD, whereas ER-positive tumours in these carriers more often retain heterozygosity and recombination proficiency; in ovarian cancers, HRD mutational signatures are more frequent with RAD51C/RAD51D than BRIP1 [13]. Known HRD causes in ovarian high-grade serous carcinoma (HGSC) include loss-of-function BRCA1, BRCA2, PALB2, RAD51C/D variants and BRCA1 and RAD51C promoter hypermethylation; approximately 50% of HGSC have HRD, with germline or somatic BRCA1/2 variants accounting for 20%–25% and epigenetic BRCA1 silencing approximately 10% [35, 36].

2.3 Variant spectrum and allelic heterogeneity

Most pathogenic variants are truncating (frameshift, nonsense, splicing), and clinically used risk estimates refer to truncating variants [13, 31]. However, practically relevant exceptions exist:

• CHEK2: the NM_007194.4:c.1100del p.(Thr367MetfsTer15) variant (historical designation c.1100delC) represented approximately 80% of BCAC truncating variants, with OR 2.66 (95% CI 2.27–3.11), not significantly different from other truncating variants (OR 2.13) [31]. Rare missense variants collectively confer OR 1.42 (1.28–1.58), regardless of location [31]. Three missense variants historically classified pathogenic — NM_007194.4:c.470T>C p.(Ile157Thr), NM_007194.4:c.1283C>T p.(Ser428Phe) and NM_007194.4:c.1427C>T p.(Thr476Met) — are now considered low-risk alleles not independently reaching actionability thresholds (CARRIERS OR 1.30 and 1.26, respectively), behaving as risk polymorphisms incorporable into PRS; when coexisting with a pathogenic variant, they are associated with a more penetrant phenotype [3, 32]. CHEK2 sequencing is technically complicated by five or more pseudogenes, and intragenic deletions/duplications may represent up to 10% of pathogenic variants, varying by population [3].
• ATM: recurrent British Isles missense NM_000051.4:c.7271T>G p.(Val2424Gly) confers breast cancer risk of 52% by 70 and 60% by 80 in older studies; UK Biobank and BCAC data showed relative risk 4.57 and OR 4.11, respectively, and GeneReviews adopts 43% risk by 80 for this variant [4]. Finnish founder NM_000051.4:c.7570G>C p.(Ala2524Pro) is also associated with high risk [4]. Other missense variants confer small risks, with excess confined to FAT and kinase domains [31]. Some deep intronic ataxia-telangiectasia variants (for example, NM_000051.4:c.5763-1050A>G) may escape exome sequencing [4].
• RAD51C/RAD51D/BRIP1: pathogenic missense variants represent less than 1% of variants reported in each gene, but French Canadian founder RAD51D NM_002878.4:c.620C>T p.(Ser207Leu) is associated with significant HGSC risk (3.8% of cases vs. 0.2% of controls), and BRIP1 NM_032043.3:c.1045G>C p.(Ala349Pro) has been described as a higher-risk non-mucinous ovarian carcinoma allele [13, 14]. BCAC found no breast cancer association with RAD51C or RAD51D missense variants [14].

2.4 Biallelic phenotypes

Biallelic ATM loss causes ataxia-telangiectasia, with approximately 1 in 300,000 prevalence according to the Oxford Desk Reference: ataxia evident when walking begins, oculomotor apraxia, scleral telangiectasias between 4 and 8 years, immunodeficiency in 80%, and lymphoma and leukaemia predisposition in 10%–30%, including 15% of those under 16; affected women have increased early breast cancer risk [1]. Biallelic PALB2, BRIP1 and RAD51C loss causes Fanconi anaemia groups N, J and O, respectively; PALB2 and RAD51C each account for less than 1% and BRIP1 approximately 2% of cases [1, 13]. Cells with biallelic BRCA2, PALB2, BRCA1 and RAD51C variants are sensitive to both DNA cross-linking agents and ionising radiation [1]. RAD51D is not currently associated with an autosomal recessive condition [13]. Individuals with biallelic CHEK2 variants (31 in a panel series; 294 in the European ERN GENTURIS series) have greater invasive breast cancer risk than heterozygotes (OR 8.69; 95% CI 3.69–20.47), more frequent diagnosis by 50 and multiple primary tumours; more than half of women with biallelic loss of function developed at least two cancers [3].

3. Clinical Spectrum and Manifestations by System

3.1 Comparative overview of gene-specific risks

The following table brings together estimates from the largest sources. Absolute risks are population averages; for all these genes, individual risk is modified by family history, PRS and hormonal factors, so the clinically observed range is wide (for example, 15%–40% for CHEK2) [3, 11].

Sources: [3, 4, 31–35, 37, 38]. In the 2024 meta-analysis of the BRIDGES, CARRIERS and UK Biobank studies (101,397 cases and 312,944 controls), ORs were 4.30 for PALB2, 2.40 for CHEK2, 2.16 for ATM, 2.34 for BARD1, 1.53 for RAD51C and 1.76 for RAD51D [39].

The Oxford Desk Reference classifies breast cancer predisposition genes as high risk (lifetime risk ≥ 40%), moderate risk (20%–39%: CHEK2, ATM, NBN, RAD50, NF1, MLH1, PIK3CA, MRE11, XRCC2) and low-risk alleles (13%–19%) [21]. Evolving evidence has changed part of this list: in CARRIERS, 16 candidate genes, including NBN (and its Slavic founder variant NM_002485.5:c.657_661del p.(Lys219AsnfsTer16), historical designation 657del5), BRIP1 and the MMR genes, were not associated with increased breast cancer risk [32]; in BCAC, 19 of the remaining 25 panel genes had an upper 95% CI limit for the OR below 2.0, the proposed threshold for moderate-risk alleles [31]. The handbook Síndromes Genéticas: Reconhecer para Tratar, adapting the 2020 NCCN guidance, assigned PALB2 a relative risk of 5.3 and an absolute risk of 45% by age 80, with an association with pancreatic cancer [40].

3.2 Entity A — breast cancer associated with moderate-penetrance genes

3.2.1 PALB2

In the international study of 524 families from 21 countries, PALB2 pathogenic variants were associated with female breast cancer (RR 7.18; 95% CI 5.82–8.85), ovarian cancer (RR 2.91), pancreatic cancer (RR 2.37) and male breast cancer (RR 7.34), with no evidence of increased risk of prostate or colorectal cancer; relative risks of breast cancer decreased with age, and estimates from multiple-case families were similar to those from population-based families after adjustment for ascertainment [33]. Dependence on family history is marked: in CARRIERS, the OR was 3.83 overall but 8.04 (5.33–12.29) in patients with a family history of breast cancer [32]. In the segregation analysis of 154 families by Antoniou and colleagues, the risk by age 70 ranged from 33% with no family history to 58% with two or more first-degree relatives affected by age 50 [41]. PALB2-associated tumours have a higher OR for ER-negative disease (OR 9.22 for ER-negative and 13.03 for triple-negative in CARRIERS) [32]. On current estimates, PALB2 is managed as a high-risk gene (absolute risk above the 30% threshold defined by NICE) [31, 36].

3.2.2 CHEK2

CHEK2-associated breast cancer is predominantly ER-positive (OR 2.67 for ER-positive vs. 1.64 for ER-negative disease in BCAC), with an association with ER-negative tumours that are not triple-negative (OR 2.53) and no association with triple-negative disease (OR 1.06) [31]. Some studies have suggested an association with HER2-positive tumours [3]. The OR is higher before age 40 (4.54) than after age 60 (2.22), and the risk of ductal carcinoma in situ is similar to that of invasive carcinoma [3, 11]. Contralateral breast cancer risk is increased (HR 2.25 in BRIDGES and 2.0 in CARRIERS), with a ten-year cumulative incidence of 13% in premenopausal women and 4% in postmenopausal women; radiotherapy has not been shown to alter this risk [3]. Prognostic data are contradictory: in a series of 2344 women diagnosed before age 40, the 53 heterozygotes had poorer overall survival (HR 1.58; 95% CI 1.01–2.48), whereas other series showed no difference [3]. In men, a meta-analysis of 26 studies found an OR of 3.13 (1.94–5.07) for breast cancer, with earlier diagnosis; prostate cancer risk is approximately doubled, with a higher prevalence of germline CHEK2 variants in metastatic disease [3]. Associations with colorectal, thyroid (Polish variant NM_007194.4:c.444+1G>A) and renal cancer are inconsistent and do not justify specific surveillance; CHEK2 does not cause Li–Fraumeni syndrome [3].

3.2.3 ATM

Breast cancer risk in ATM heterozygotes primarily concerns ER-positive tumours, with no evidence of increased risk of ER-negative tumours (OR 2.33 vs. 1.01 in BCAC), and the OR remains stable with age [4, 31]. No increase in contralateral risk was observed, which may reflect the limited number of patients studied or the efficacy of adjuvant endocrine therapy [4]. The extramammary spectrum includes pancreatic ductal adenocarcinoma, with cumulative risks of 1.1% by age 50, 6.3% by age 70 and 9.5% by age 80 and a mean age at diagnosis of 64 years; prostate cancer, with an OR of 4.4 and a higher frequency of germline variants in aggressive (1.6%) and metastatic (1.9%) disease than in non-aggressive disease (0.7%); and gastric adenocarcinoma, with an OR of 2.97 in a laboratory series and 5.50 in BioBank Japan, an association apparently modulated by Helicobacter pylori infection [4]. Associations with ovarian cancer (OR 1.57), colorectal cancer (1.49) and melanoma (1.46) are modest and unconfirmed [4]. The ESMO Handbook gives absolute risks for ATM of 20%–30% for breast, 2%–3% for ovarian and approximately 5%–10% for pancreatic cancer [35].

3.2.4 BARD1

BARD1 is predominantly associated with ER-negative and triple-negative breast cancer. In BCAC, the overall association had an OR of 2.09, with a stronger association for triple-negative tumours [31]; in CARRIERS, the overall association was not significant (OR 1.37), but there was a moderate risk of ER-negative and triple-negative disease [32]. The meta-analysis of approximately 48,700 breast cancer cases and 134,100 gnomAD controls obtained an OR of 2.90 (2.25–3.75) for breast and 1.36 (0.87–2.11) for ovarian cancer, concluding that BARD1 is not an ovarian risk gene [37]. The ESMO Handbook reports an absolute breast cancer risk of 17%–30% and no established association with ovarian cancer [35].

3.2.5 RAD51C and RAD51D in breast cancer

Breast cancer risk associated with RAD51C and RAD51D is moderate (RR 1.99 and 1.83; approximately 20% by age 80), confined to truncating variants and concentrated in ER-negative and triple-negative tumours; with two first-degree relatives with breast cancer, risk may reach 44%–46% [14, 34]. Even in triple-negative cancer, pathogenic variants in these genes (and in BRIP1) are rare (0.3%–0.5%) [13]. Limited data show no increase in contralateral risk or association with disease-specific survival [13].

3.3 Entity B — hereditary ovarian cancer outside the BRCA1/2 context

3.3.1 Overall contribution and histology

Germline variants in BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer [14]; the ACMG resource estimates that approximately 20% of ovarian cancer has a monogenic cause, mainly BRCA1/2, with less than 3% attributable to MMR genes [13]. In a meta-analysis of 63 studies, prevalence in patients with ovarian cancer was 0.6% for RAD51C, 0.5% for RAD51D and 0.9% for BRIP1, compared with 0.05%, 0.05% and 0.15% in BRIDGES controls [13]. Among ovarian cancer patients tested in two US states, detection rates were 0.4% for PALB2, 0.58% for RAD51C, 0.48% for RAD51D and 0.92% for BRIP1, compared with 8.7% for BRCA1 and 5.8% for BRCA2 [42]. BRIP1 is the most frequent finding after BRCA1/2 in patients with ovarian cancer in a single-centre British series [13].

Tumours associated with RAD51C, RAD51D, BRIP1 and PALB2, like those associated with BRCA1/2, are predominantly HGSC [14]. In population studies, approximately 1.2% of HGSC and endometrioid carcinomas and 0.8% of low-grade serous carcinomas have a germline BRIP1 variant; 0.4%–0.5% of HGSC, endometrioid and clear-cell carcinomas have a RAD51C variant; and RAD51D was found in 0.5% of HGSC and 0.9% of endometrioid carcinomas; none of these genes was identified in mucinous carcinomas [13]. Mucinous and clear-cell carcinomas are overrepresented in Lynch syndrome, and borderline and mucinous tumours should not be counted when assessing the probability of BRCA1/2 [21, 22]. Approximately 15% of endometrioid and clear-cell ovarian carcinomas show MMR deficiency [36].

3.3.2 RAD51C and RAD51D

In the analysis of 6178 families (125 with RAD51C) and 6690 families (60 with RAD51D), the relative risk of tubo-ovarian carcinoma was 7.55 and 7.60, with cumulative risks by age 80 of 11% (6%–21%) and 13% (7%–23%); relative risk appeared to increase with age up to approximately 60 and decline thereafter, and with two first-degree relatives with ovarian cancer, risk reached 32%–36% [34]. Risk by age 50 is 1% for RAD51C and 0.8% for RAD51D; ten-year risk peaks between ages 50 and 60 (RAD51C) and between ages 50 and 70 (RAD51D) [14]. In a series of carriers identified by multigene panel testing, median age at ovarian cancer diagnosis was 62 years for RAD51C and 57 years for RAD51D, with 82.6% and 77.5% of cases occurring after age 50 [43].

3.3.3 BRIP1

In the study of 3236 invasive epithelial ovarian cancer cases and 3431 controls, deleterious BRIP1 variants were present in 0.9% of cases and 0.09% of controls, with a relative risk of 11.22 for invasive cancer and 14.09 for HGSC; family segregation analysis estimated a mean relative risk of 3.41 and a cumulative risk by age 80 of 5.8% [38]. The meta-analysis of studies published up to 2019 obtained an OR of 4.94 (4.07–6.00) [44]. The ACMG resource notes that the cumulative risk of 5.8% may be underestimated because the control group included high-risk women from UKFOCSS screening, and that a British series suggests lifetime risks of 7%–10%, comparable to those for RAD51C/D [13]. BRIP1-associated ovarian cancer occurs late: mean age 63.8 years (58 in non-carriers) and median age 65 years, with 90.1% of diagnoses after age 50 [38, 43]. BRIP1 is not associated with breast cancer (OR 1.11 in BCAC) [31].

3.3.4 PALB2 in ovarian cancer

The relative risk of ovarian cancer in PALB2 carriers is 2.91, with a risk of 0.6% by age 50 and 5% (2%–10%) by age 80; another study estimated 3.2% by age 80 and an OR of 3.01 for HGSC [14, 33, 45]. With a mother and sister affected at age 50, lifetime risk is 16% (8%–28%) [14]. According to the CanRisk multifactorial model, 62% of PALB2 carriers have a lifetime ovarian cancer risk below 5%, 35% between 5% and 10%, and 3% above 10% [18].

3.3.5 MMR genes (Lynch syndrome)

The risk of ovarian cancer by age 65 is 8% for MLH1, 11% for MSH2, 3% for MSH6 and 2.5% for PMS2, compared with 0.5% in the general population; median age at diagnosis is 47–49 years for MLH1 and MSH2, 65 years for MSH6 and 57 years for PMS2, and most tumours are of endometrioid histology [7]. The Oxford Desk Reference estimates the lifetime risk of ovarian cancer at about 10% for the MMR genes, BRIP1, RAD51C and RAD51D [22]. Gynaecological management of Lynch syndrome includes hysterectomy with bilateral salpingo-oophorectomy.

3.3.6 Genes without an established ovarian association

CHEK2 has no association with ovarian cancer, so salpingo-oophorectomy is not recommended on the basis of genotype [11]; for ATM, the ESMO Handbook reports an absolute risk of 2%–3% and insufficient evidence for routine risk-reducing surgery [35]; BARD1 is not an ovarian risk gene, and ClinGen classifies the BARD1–familial ovarian cancer relationship as disputed [8, 37].

4. Clinical Recognition and Warning Signs

The classic autosomal dominant pattern (several affected individuals in successive generations) is frequently absent in these families because intermediate penetrance means there are cancer-free carriers in every generation [3, 4]. Suspicion should be guided by tumour phenotype and the combination of malignancies in the family:

A family with a single ovarian cancer case warrants cautious interpretation: relative risk for a first-degree female relative is approximately 3.1, corresponding to a cumulative risk of 4% by age 70 in Northern Europe and North America; very early onset is not characteristic of familial ovarian cancer (only 1.6% of 202 families with at least two confirmed cases had a diagnosis before age 30, and none of 101 women diagnosed before age 30 had a BRCA1/2 variant) [22]. An ovarian cancer diagnosis reported by the family should be confirmed because it is frequently incorrect (benign lesion, teratoma, intestinal adenocarcinoma, uterine cancer, Krukenberg tumour), whereas breast cancer diagnoses in close relatives rarely are [21, 22]. Identification of a variant on a tumour panel may be the first sign: in an analysis of 45,472 solid tumours, 89.9% of filtered CHEK2 variants were germline, compared with 52.6% of ATM variants (72.6% in breast and 33.3% in colorectal cancers) [3, 4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Indications for testing

Applicable germline testing criteria include those of NCCN, NICE and the British National Health Service panels. The specific point of this article is that multigene panels have replaced gene-by-gene testing, and that applying the classic criteria would miss up to 50% of carriers; several guidelines recommend BRCA1/2 testing in all patients with breast cancer up to age 65, recognising that, between 50 and 65 years, most variants identified will be in moderate-penetrance genes, and universal testing is recommended for ovarian, pancreatic and high-risk or metastatic prostate cancer [35]. In CARRIERS, about 3.3% of women with ER-positive breast cancer and no family history had a pathogenic variant in an actionable gene, mainly ATM, CHEK2 and BRCA2 [32]. ESMO recommends germline and/or somatic BRCA1/2 testing and HRD testing at diagnosis of all high-grade non-mucinous epithelial ovarian carcinomas [36]. In the United Kingdom, the National Genomic Test Directory includes PALB2 in the hereditary breast and ovarian cancer panel (R208) and RAD51C, RAD51D and BRIP1 in the familial ovarian cancer panel (R207), and the UKCGG decided that the breast panel genes should be the same whether the test is requested by oncology (mainstreaming) or by clinical genetics [14]. The Oxford Desk Reference recommends considering RAD51C/RAD51D testing in families at high risk of ovarian cancer and MMR gene testing when the family meets the Amsterdam criteria [22].

5.2 Methods and technical limitations

Diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic germline variant; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [3, 4]. Sequencing detects 89%–93% of pathogenic CHEK2 variants and 90%–95% of ATM variants; targeted deletion/duplication analysis (MLPA, quantitative PCR, exon microarray) adds up to 10% and 5%–10%, respectively [3, 4]. Approximately half of ClinVar entries for RAD51C (47.2%), RAD51D (45.6%) and BRIP1 (51.1%) are VUS, predominantly missense [13]. Detection of a CHEK2 or ATM variant with a low allele fraction in leucocytes suggests clonal haematopoiesis of indeterminate potential (CHIP), cytotoxic therapy, haematological malignancy or circulating tumour cells, and even fractions in the heterozygous range may be acquired; confirmation in another tissue (for example, cultured fibroblasts) may be necessary, and an individual whose variant results solely from CHIP does not have hereditary predisposition [3, 4].

5.3 Interpretation and reporting

The ENIGMA group (Evidence-based Network for the Interpretation of Germline Mutant Alleles) proposes that only variants associated with at least a twofold risk should be reported as clinically relevant [3, 13]. Practical rules follow: low-risk CHEK2 variants (NM_007194.4: p.(Ile157Thr), p.(Ser428Phe), p.(Thr476Met)) should not guide surveillance, which is based on family history; ACMG considers that most missense CHEK2 variants should not routinely be reported in tumour or germline testing [11]. For ATM, the UKCGG reporting practice statement (v2.2) recommends that, in diagnostic testing for an oncological indication, British National Health Service laboratories restrict reporting to canonical truncating variants and NM_000051.4:c.7271T>G; the ClinGen expert panel published specifications of the ACMG/AMP rules for ATM (version 1.4.0, July 2025) [4]. VUS should not guide clinical decisions or predictive testing of relatives, and the possibility of reclassification should be discussed with the patient [11].

5.4 Variants identified on tumour panels

Based on 17,152 samples with paired sequencing, the ESMO Precision Medicine Working Group recommended restricting germline-focused analysis to variants with an allele fraction above 30% (single-nucleotide variants) or 20% (small insertions/deletions); in the “off-tumour” context (a gene with no known association with the tumour type), analysis should be limited to highly actionable genes, which include BRCA1/2, BRIP1, PALB2, RAD51C/D and the MMR genes, with genes of standard actionability restricted to the “on-tumour” context [35]. ACMG acknowledges the high probability that a CHEK2 variant identified in the tumour is present in the germline and the NCCN recommendation for germline confirmation when there is potential clinical significance [11].

5.5 Risk assessment algorithm

The Oxford Desk Reference recommends stratifying familial breast cancer risk into three classes (near-population, moderate and high risk), using a calculation method with demonstrated calibration and discrimination whenever possible, such as BOADICEA, and, in its absence, the histology-adjusted Manchester score and family-history triage [21]. The sequence proposed by this article, consistent with the ACMG resources and UKCGG consensus, is as follows: (1) confirm variant classification and type (truncating or missense, low-risk allele, high-risk variant such as ATM NM_000051.4:c.7271T>G); (2) exclude CHIP or mosaicism if suggested by allele fraction; (3) calculate individual breast and ovarian cancer risk in CanRisk using family history and, when available, hormonal factors, mammographic density and PRS; (4) apply the country's surveillance and surgery thresholds (section 7); (5) offer cascade testing and calculate residual risk in non-carrier relatives [11–14].

5.6 Multifactorial estimation: PRS and CanRisk

More than 100 common variants in non-coding DNA are associated with small increases in breast cancer risk, and the actual number is expected to approach a thousand; in 2015, a PRS comprising 77 polymorphisms separated lifetime risks of 5.2% and 16.6% (lowest and highest quintiles) in women without a family history, and 8.6% and 24.4% in women with one affected first-degree relative [21]. The 313-polymorphism PRS (PRS313), developed in 94,075 cases and 75,017 controls of European ancestry, has an OR of 1.61 per standard deviation and an area under the curve of 0.630; lifetime risk in the highest centile is 32.6%, and in the top 1%, risk is 4.37 times (ER-positive) and 2.78 times (ER-negative) that of the middle quintile [46]. The BOADICEA v6 model, integrated into CanRisk, combines truncating variants in BRCA1, BRCA2, PALB2, CHEK2 and ATM, PRS313, a residual polygenic component, hormonal, reproductive and lifestyle factors, and mammographic density; with all factors included, predicted lifetime risks for the British population range from 2.8% (centile 1) to 30.6% (centile 99) [16, 17]. In 2022, the model was extended to BARD1, RAD51C and RAD51D (with 34%–44% of these carriers reclassified to near-population risk and 15%–22% to high risk according to NICE categories), and the epithelial ovarian cancer model began to include PALB2 [18]. Prospective validation in the Swedish KARMA cohort (66,415 women) showed good calibration and an area under the curve of 0.70 with all factors, with PRS contributing most to stratification [47].

PRS modifies risk more in moderate-gene carriers than in BRCA1/2 carriers: the OR per standard deviation of an 86-polymorphism PRS was 1.49 in CHEK2 carriers and 1.37 in ATM carriers, compared with 1.20 and 1.23 in BRCA1 and BRCA2 carriers [48]. Combining PRS, the Tyrer-Cuzick model and genotype, remaining lifetime risk was low (≤ 20%) in 24.2% of CHEK2 carriers and 31.5% of ATM carriers, and high (> 50%) in 12.0% and 9.7%, respectively [49]. In Dutch families with CHEK2 c.1100delC, adding PRS311 to family history changed the surveillance category of 37.9% of heterozygotes and 32.2% of non-carriers, moving most heterozygotes to less intensive surveillance and some non-carriers to more intensive surveillance [50]. For an average 20-year-old RAD51C carrier without a family history, the multifactorial model classifies 38% at population risk, 43% at moderate risk and 19% at high risk; with a mother affected at age 50, these proportions become 15%, 42% and 43% [14].

There are limitations to consider. ACMG considers that using PRS to guide management should, for now, be limited to clinical trials, and that heterogeneity among available PRS hampers implementation [11]. CanRisk uses estimates derived from truncating variants, so it underestimates the risk associated with higher-penetrance missense variants (such as ATM c.7271T>G) and may overestimate risk from missense RAD51C/D variants [4, 13]. PRS313 has been validated in populations of European ancestry [46, 51].

5.7 Limits of genetic testing and report content

A negative result is informative only if test coverage is known. The report should state whether all coding regions and exon–intron junctions were analysed, whether copy number variation was investigated (deletions and duplications of one or more exons, representing up to 10% of pathogenic CHEK2 variants and 5%–10% of ATM variants), by which method, and which regions had reduced coverage [3, 4]. In CHEK2, the existence of five or more pseudogenes can complicate sequencing, depending on the methodology used, so the laboratory should state how it resolved homologous regions [3]; in ATM, deep intronic variants such as NM_000051.4:c.5763-1050A>G escape exome sequencing and panels that do not include the corresponding intronic regions [4]. Sensitivity for mosaicism and the distinction between a constitutional variant and clonal haematopoiesis (CHIP) should be explicit, as described in section 5.2 [3, 4]. A variant identified only on a tumour panel requires germline confirmation, and a negative germline test does not exclude tumour HRD from a somatic or epigenetic cause, such as RAD51C promoter methylation [35, 36].

The report should contain the gene, versioned reference transcript, Human Genome Variation Society (HGVS) nomenclature at coding DNA and protein levels, zygosity (and, with two variants in the same gene, phase, because compound heterozygosity or homozygosity in ATM, PALB2, BRIP1 or RAD51C has its own implications), classification according to ACMG/AMP criteria with the criteria applied, and technical limitations [4, 13]. The MANE Select transcripts are NM_007194.4 (CHEK2), NM_024675.4 (PALB2), NM_000051.4 (ATM), NM_000465.4 (BARD1), NM_058216.3 (RAD51C), NM_002878.4 (RAD51D) and NM_032043.3 (BRIP1) [52]. The literature frequently uses historical designations that the report should convert to the standardised form, retaining the old form only as an equivalence: the “CHEK2 1100delC” variant corresponds to NM_007194.4:c.1100del, p.(Thr367MetfsTer15) (ClinVar VCV000128042, pathogenic), and the Polish “IVS2+1G>A” variant to c.444+1G>A (VCV000128075) [53]. ClinVar classification illustrates different evidence levels: ATM c.7271T>G, p.(Val2424Gly) (VCV000003023) was reviewed by an expert panel and classified as pathogenic; CHEK2 c.470T>C, p.(Ile157Thr) (VCV000005591) has conflicting classifications and the designation of risk factor, consistent with its status as a low-risk allele; RAD51D c.620C>T, p.(Ser207Leu) (VCV000142102) and c.694C>T, p.(Arg232Ter) (VCV000127893), and BRIP1 c.1045G>C, p.(Ala349Pro) (VCV000030535), are pathogenic or likely pathogenic, with several concordant submissions [53]. The Icelandic BRIP1 variant is cited in section 9.2 as published (c.2040_2041insTT) [30].

A variant of uncertain significance does not become pathogenic because of a tumour response to a PARP inhibitor or partial segregation in a family. In this group of incompletely penetrant genes, segregation is particularly uninformative because there are healthy carriers and phenocopy cases (sporadic breast cancer) in almost every family; studying relatives to clarify a variant of uncertain significance is research rather than predictive testing, and the variant should not guide surveillance, risk-reducing surgery, cascade testing, prenatal diagnosis or preimplantation genetic testing [3, 11, 13]. Reclassification should be requested from the laboratory when new evidence emerges and communicated to the patient (section 11) [11].

6. Differential Diagnosis

CHEK2 predisposition cannot be clinically distinguished from other susceptibility syndromes solely by the constellation of tumours and ages of onset; molecular testing is indispensable [3].

7. Treatments and Risk Management Strategies

7.1 General principle

Management of these genes differs from BRCA1/2 management because risk is continuous and strongly modified by other factors. The ACMG resources for CHEK2 and ATM emphasise that, although these are moderate-penetrance genes, risks should be viewed as a continuous variable influenced by family history and other modifiers, and that personalised estimation can either lower risk to near-population values or raise it to a level warranting high-risk surveillance [11, 12]. The ESMO Handbook emphasises that, for PALB2 and ATM, the indication for salpingo-oophorectomy is particularly controversial because ovarian risk depends on family history and should be assessed individually [35].

7.2 Gene-specific surveillance and risk-reducing surgery

7.3 Rationale for breast surveillance

The benefit of MRI in moderate-gene carriers is based mainly on modelling. The CISNET analysis for ATM, CHEK2 and PALB2 estimated mean lifetime risks of 20.9%, 27.6% and 39.5%; annual mammography from age 40 to 74 would reduce breast cancer mortality by 36%–39%, and annual MRI from age 30–35, followed by MRI and mammography from age 40, by 54%–60%, at the cost of approximately 4700 to 5400 false positives and 1300 to 1500 benign biopsies per 1000 women; with MRI from age 30, starting mammography before age 40 added no significant benefit [54]. For BARD1, ClinGen emphasises that evidence of surveillance efficacy is extrapolated from BRCA1/2 carriers and women with a family history [8]. In RAD51C/D carriers, the higher proportion of triple-negative tumours, with lower mammographic sensitivity and more interval cancers, justifies considering MRI when applicable [13]. British stratification follows NICE CG164, in which moderate risk (17%–30% lifetime; 3%–8% between ages 40 and 50) provides access to annual mammography from age 40 to 49 and high risk (≥ 30%) to annual mammography up to age 59, while annual MRI is reserved for BRCA1/2/TP53 carriers and those with a probability above 30% of carrying these variants; MRI is not routinely offered to moderate-risk groups [55, 56]. The NHS VHR programme (annual mammography and MRI from age 25–30 to 70) requires lifetime risk ≥ 40% due to a specific genetic alteration, demonstrated in CanRisk by ten-year risks above 8% between ages 25 and 39 or 12% between ages 40 and 49 [14].

In women who already have breast cancer, contralateral risk-reducing mastectomy should not routinely be offered to CHEK2 heterozygotes; it may be considered after personalised assessment weighing age at diagnosis, competing risk from the first tumour and the risk reduction conferred by adjuvant endocrine therapy, with intensive surveillance of the remaining breast tissue as the alternative [3, 11]. A 2026 meta-analysis of the BRIDGES and CARRIERS cohorts estimated ten-year cumulative contralateral breast cancer risks of 8.0% (95% CI 5.7–11.1) for CHEK2 carriers (8.5% for NM_007194.4:c.1100del), 7.1% (3.4–14.3) for PALB2 and 4.5% (2.5–8.0) for ATM, compared with 10.1% and 10.2% for BRCA1 and BRCA2; the hazard ratio was significant for CHEK2 (2.1; 95% CI 1.6–2.9), particularly after a first ER-positive tumour, but not for PALB2 (1.9; 0.9–3.8) or ATM (1.2; 0.7–2.1), with increased risk in PALB2 carriers after an ER-negative tumour [57]. These values, calculated using Dutch population rates, support shared decision-making rather than a systematic indication for contralateral mastectomy.

7.4 Risk-reducing gynaecological surgery

There is no ovarian cancer screening method with demonstrated benefit: UKCTOCS did not reduce mortality in the general population, and UKFOCSS, in high-risk women, showed only a stage shift [14]. CA-125 measurement and pelvic ultrasound are not recommended outside trials [22]. The risk threshold for discussing RRSO is based on British cost-effectiveness analyses that justify it above a lifetime risk of 4%–5%; the United Kingdom adopts 5%, and the USA proposes 3%–4% [4, 14]. For RAD51C, RAD51D, BRIP1 and PALB2, almost all carriers have a risk below 3% before age 50 (99.6%, 99.9%, 99.7% and 100% without a family history, respectively), supporting age 50 as the reference and consideration of earlier surgery only after individual assessment, including menopausal symptoms and shared decision-making [14]. Median ages at diagnosis (62, 57 and 65 years for RAD51C, RAD51D and BRIP1) are comparable to that in the general population (63 years) [13].

Surgery should be salpingo-oophorectomy rather than isolated oophorectomy because high-grade serous carcinomas predominantly originate in the tubal fimbria, with precursor lesions of the serous tubal intraepithelial carcinoma (STIC) type; a residual risk of primary peritoneal carcinoma persists [22, 35]. The specimen should be examined according to the SEE-FIM protocol (Sectioning and Extensively Examining the Fimbria); in a small series of RAD51C, RAD51D and BRIP1 carriers undergoing RRSO, there were no occult carcinomas and one STIC was recorded in a BRIP1 carrier [13]. Early salpingectomy with delayed oophorectomy is being evaluated (WISP, TUBA, PROTECTOR and SOROCk studies) and, for these genes, should only be offered in research [14, 35].

Premenopausal oophorectomy causes abrupt menopause, with hot flushes, sleep disturbance, vaginal dryness, sexual dysfunction, osteoporosis, increased cardiovascular risk, depression, anxiety, cognitive decline and multimorbidity; hormone replacement therapy alleviates some, but not all, of these consequences, and preoperative discussion should detail these effects [14, 22]. RRSO is recommended only after completion of childbearing [14].

7.5 Endocrine chemoprevention

There are no gene-specific chemoprevention data for these genes. Given the predominance of ER-positive tumours in ATM and CHEK2 carriers, risk-reducing endocrine therapy (tamoxifen, raloxifene or anastrozole) may be considered in the context of family history and personalised risk [4]. The following doses come from official labels or the supporting trial:

7.6 Systemic treatment of established malignancies

For none of these genes is there sufficient evidence to justify changing standard cancer treatment on the basis of the germline result, except in the regulatory contexts described below [3, 4, 13]. PARP inhibitors exploit synthetic lethality in HRD tumours [35].

Metastatic castration-resistant prostate cancer (mCRPC). Olaparib (Lynparza®) is FDA-approved, at an oral dose of 300 mg twice daily (200 mg twice daily in moderate renal impairment) with a concomitant GnRH analogue or orchiectomy, for mCRPC with a germline or somatic variant in one of 14 HRR genes — including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD51C and RAD51D — following progression on enzalutamide or abiraterone [64]. In Europe, the equivalent indication is restricted to BRCA1/2 variants [65]. Talazoparib (Talzenna®) is FDA-approved, at 0.5 mg once daily in combination with enzalutamide, for mCRPC with alterations in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 or RAD51C; in Europe, tumour mutation testing is not required for this indication [66, 67]. Evidence of efficacy in non-BRCA genes is limited: approval data primarily concerned BRCA2, and the talazoparib–enzalutamide combination showed no significant benefit in the ATM subgroup [4, 12]. Current labels quantify this difference in exploratory analyses: in PROfound cohort B (HRR genes other than BRCA1, BRCA2 or ATM, including CHEK2, PALB2, BRIP1, BARD1 and RAD51D), median radiographic progression-free survival was 4.8 versus 3.3 months (HR 0.88; 95% CI 0.58–1.36), with objective responses of 3.7% versus 8.3% [64]; in TALAPRO-2, the radiographic progression-free survival HR was 0.20 (95% CI 0.11–0.36) in the BRCA variant subgroup and 0.74 (95% CI 0.50–1.09) in the remaining HRR genes, and the overall survival HR was 0.48 and 0.71 (95% CI 0.51–1.00), respectively [66]. In metastatic castration-sensitive prostate cancer, the phase 3 AMPLITUDE trial (696 patients with HRR gene alterations) led to FDA approval of niraparib plus abiraterone acetate (Akeega®) in December 2025, only for BRCA2 variants, because in the exploratory subgroup of 373 patients without a BRCA2 variant, the radiographic progression-free survival HR was 0.88 (95% CI 0.63–1.24); in the EU, the current SmPC (latest European Commission decision on 14 August 2026) limits the indication to BRCA1/2 variants [68, 69]. ACMG currently advises against selecting PARP inhibitors on the basis of CHEK2, because associated tumours do not exhibit HRD [11].

Ovarian cancer. PARP inhibitor indications in ovarian cancer are defined by BRCA and/or HRD status, rather than by RAD51C, RAD51D, BRIP1 or PALB2 [64, 70]. Olaparib in combination with bevacizumab is indicated for first-line maintenance of advanced HRD-positive carcinomas (BRCA variant and/or genomic instability) [64]; niraparib (Zejula®) is FDA-approved for first-line maintenance of advanced HRD-positive carcinomas, at 200 mg daily (weight < 77 kg or platelets < 150,000/µL) or 300 mg daily (weight ≥ 77 kg and platelets ≥ 150,000/µL), whereas in the European Union first-line maintenance and maintenance of platinum-sensitive recurrence do not require a biomarker [70, 71]. The US restriction of first-line treatment to HRD-positive status was introduced in the label in March 2026 (the April 2020 approval, based on the PRIMA trial, did not require a biomarker); in the current label, the final overall survival analysis in the PRIMA HRD-positive subgroup showed an HR of 0.95 (95% CI 0.71–1.29), with medians of 71.9 and 69.8 months, despite the progression-free survival benefit (HR 0.43) [70, 72]. In PAOLA-1, exploratory analysis of HRD-negative tumours showed no benefit (progression-free survival HR 1.00; 95% CI 0.75–1.34) [64]. ESMO classifies somatic PALB2, ATM, CHEK1/2 and RAD51B/C/D alterations in gynaecological cancers as ESCAT levels IIIB/IVA (hypothetical targets) [36]. Tumours with RAD51C/D variants more frequently show HRD signatures and may therefore be classified as HRD-positive on tumour testing [13].

Breast cancer. PARP inhibitors are approved only for carriers of germline BRCA1/2 variants [64, 66]. Germline PALB2 variants are an ESCAT IIB target for olaparib, based on the phase II TBCRC 048 trial, which showed efficacy in PALB2 carriers and patients with somatic BRCA1/2 variants; somatic ATR/ATM/PALB2 alterations are ESCAT IVA [36]. In the original publication, confirmed responses were limited to germline PALB2 (82%) and somatic BRCA1/2 variants (50%), with no responses in isolated ATM or CHEK2 variants [73]; in the expansion cohorts published in 2026 (54 patients, including 24 with a germline PALB2 variant; 78% with ER-positive, HER2-negative disease), objective response in PALB2 carriers was 75% (80% CI 60.2–86.3), with median progression-free survival of 9.4 months [74]. These phase II data support olaparib use in these patients, but use is off-label, since the US and EU indications require a germline BRCA1/2 variant [64, 65]. ACMG recommends considering PALB2 carriers for the same regimens and trials as BRCA1/2 carriers [10]. The European RADIOLA trial evaluates olaparib in advanced HER2-negative breast cancer with a variant in BRCA1, BRCA2, PALB2, RAD51C or RAD51D, or functional HRD (RAD51 score ≤ 10%) [13].

Adverse effects of PARP inhibitors. Myelodysplastic syndrome/acute myeloid leukaemia (approximately 1.2% of patients exposed to olaparib, mostly fatal) — baseline and monthly full blood count and permanent discontinuation if confirmed; pneumonitis (1.0%) — interrupt if suspected and discontinue if confirmed; venous thromboembolism (8% in mCRPC); hepatotoxicity; anaemia, nausea, fatigue and vomiting as common effects [64]. Talazoparib causes myelosuppression (anaemia, neutropenia, thrombocytopenia) and carries a risk of embryo-fetal toxicity [66]. Niraparib requires a weekly full blood count in the first month and monthly in the following 11 months, and blood pressure and heart rate monitoring [70].

Radiotherapy. Extreme radiation sensitivity is a feature of ataxia-telangiectasia rather than heterozygotes: ATM-heterozygous women with breast cancer did not have more acute or late toxicity after radiotherapy, there is no evidence of increased second primaries after adjuvant radiotherapy, and ACMG recommends that the genetic result should not influence the radiotherapy decision [4, 12]. The Oxford Desk Reference (2017) advised avoiding regular mammography in ataxia-telangiectasia heterozygotes (3.6-fold breast cancer risk) and minimising diagnostic radiographs [1]; this recommendation has been superseded by current resources, which include annual mammography from age 40 [4, 12].

7.7 Pivotal trials and limits of comparisons between trials

No randomised trial was designed for carriers of germline variants in CHEK2, PALB2, ATM, BARD1, RAD51C, RAD51D or BRIP1. Available evidence comes from trial subgroups in populations defined by tumour alterations (germline or somatic) in HRR genes, tumour HRD or clinical breast cancer risk, and from single-arm phase II trials.

These results do not permit ranking drugs or genes by indirect comparison. Prostate cancer trials differ in disease phase (castration-sensitive or resistant), comparator (endocrine therapy alone or a change in endocrine therapy), origin of the alteration (predominantly tumour-derived, germline or somatic) and gene list, and in all trials benefit was concentrated in patients with a BRCA1/2 variant, while results in other genes were exploratory, with confidence intervals including no effect; a favourable overall hazard ratio in an HRR population cannot be transferred to CHEK2, ATM or PALB2 individually [64, 66, 68]. In ovarian cancer, the progression-free survival benefit in the PRIMA HRD-positive subgroup was not accompanied by an overall survival gain, whereas PAOLA-1 showed a gain in the HRD-positive subgroup; the populations, comparator (placebo alone or with bevacizumab) and HRD tests differ, and neither trial analysed RAD51C, RAD51D, BRIP1 or PALB2 carriers as a distinct group [64, 70]. TBCRC 048 response rates come from single-arm trials with 80% or 90% confidence intervals and small samples and are not comparable with those from randomised trials [73, 74]. In chemoprevention, relative reductions should be read alongside the absolute rate: in IBIS-II, a relative reduction of approximately half corresponded to a 2.8-percentage-point difference in predicted seven-year cumulative incidence, without a mortality difference, and none of these trials stratified results by germline variants in moderate-penetrance genes [58, 62].

7.8 Comparative regulatory status, evidence hierarchy and access

The strength of information differs by source: peer-reviewed publication (for example, TBCRC 048), exploratory subgroup results described in the label, sponsor press release, regulatory opinion or authorisation decision. In the European Union, a favourable CHMP opinion is not yet an authorisation, which exists only after the European Commission decision, and an authorisation, whether European or US, does not guarantee marketing, reimbursement or access in each country; in Portugal, access depends on marketing and INFARMED's funding assessment, and in Brazil on ANVISA registration and, within the Unified Health System, incorporation following CONITEC assessment [75]. The table summarises, as of 4 October 2026, label differences with consequences for carriers of variants in moderate-penetrance genes.

7.9 Evidence extrapolation and off-label use

Extrapolation and off-label use are different dimensions. Extrapolation applies a benefit demonstrated in BRCA1/2 carriers or HRD-positive tumours to PALB2, RAD51C or RAD51D carriers on the basis of a shared mechanism; off-label use is defined by label wording, age, sex and jurisdiction. Thus, olaparib in a patient with metastatic breast cancer and a germline PALB2 variant is extrapolation supported by phase II data and is off-label in the USA and EU [64, 65, 74]; the same drug in a man with mCRPC and a PALB2 variant is within the US indication and outside the European indication [64, 65]. In chemoprevention, anastrozole is off-label in both jurisdictions and raloxifene in the EU, while tamoxifen depends on the national SmPC [58, 60, 62, 75]. PARP inhibitors and endocrine chemoprevention are contraindicated or discouraged during pregnancy because of the embryo-fetal toxicity described in labels, and trials did not include pregnant women [58, 64, 66]. None of these drugs has a paediatric indication in the context of this article, and predictive testing of these genes is not recommended in minors (section 8). When off-label use is considered, the dose should be that of the supporting trial (in TBCRC 048, olaparib 300 mg twice daily), and the use should be identified as such [73].

8. Reproductive Options and Family Counselling

All these genes follow autosomal dominant inheritance for cancer predisposition, with a 50% risk of transmission to each child; most probands inherited the variant from a parent who may not have had cancer, depending on penetrance, sex, age, risk reduction through surgery or surveillance, and early death [3, 4]. Testing should be offered to both parents to determine the family branch at risk [3].

Predictive testing of a non-carrier relative has a different meaning from that observed in high-penetrance genes: a negative result for a familial CHEK2, RAD51C, RAD51D or BRIP1 variant does not necessarily reduce risk to the population level, because familial aggregation may depend on other factors; residual risk should be calculated (particularly breast risk, in CanRisk) and surveillance adjusted [11, 13]. Predictive testing is not recommended in minors, because these are adult risks and to preserve autonomy [3, 13].

Recessive phenotypes require partner counselling. For ATM, testing the reproductive partner should be considered because a heterozygous couple has a 25% risk of a child with ataxia-telangiectasia; in this case, testing a minor at risk of a biallelic genotype should be offered because it alters childhood management [4]. The frequency of ATM heterozygotes is approximately 1 in 200, so without consanguinity the risk to the extended family is low — for example, 1/1200 for a healthy sibling of a patient with ataxia-telangiectasia and 1/1600 for an uncle [1]. For RAD51C (carrier frequency approximately 1 in 1600), the probability of a child with Fanconi anaemia is approximately 1 in 6400, and for BRIP1 (1 in 500), approximately 1 in 2000; the English National Health Service funds partner testing only when population carrier frequency exceeds 1 in 70 [13]. For PALB2, a heterozygous couple has a 25% risk of a child with FA-N Fanconi anaemia, whose spectrum includes early solid tumours [2]. For CHEK2, if both parents are heterozygous, the probability of a sibling inheriting at least one variant is 75% [3].

Prenatal diagnosis and preimplantation genetic testing (PGT-M) are technically possible once the familial variant has been identified, but for moderate-penetrance, adult-onset genes they constitute a complex discussion that should be conducted by experienced professionals, ideally before pregnancy [3, 11, 13]. Prenatal diagnosis of ataxia-telangiectasia is usually possible by chorionic villus sampling at 11 weeks in families with known variants [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Population frequency

In the BRIDGES/CARRIERS/UK Biobank meta-analysis, the frequency of pathogenic variants in unselected breast cancer cases was 1 in 73 for CHEK2, 1 in 132 for ATM, 1 in 187 for PALB2, 1 in 672 for BARD1, 1 in 913 for RAD51C and 1 in 1079 for RAD51D; ATM was present in 0.76% of cases and 0.35% of controls [4, 39]. The ESMO Handbook estimates that approximately 10% of breast cancers are hereditary, with approximately 3% of variants in high-risk genes, approximately 3% in moderate-risk genes (ATM and CHEK2) and approximately 4% with unidentified genetic factors [36]. In CARRIERS, variants in 12 established genes were present in 5.03% of cases and 1.63% of controls [32].

9.2 Founder and recurrent variants

The frequency of ATM heterozygotes (gnomAD v3.1) is 1/142 in Latino/admixed Americans, 1/277 in non-Finnish Europeans, 1/357 in Africans/African Americans, 1/370 in East Asia, 1/434 in Ashkenazi Jews and 1/1204 in South Asia [4].

9.3 Population differences and data gaps

The effect size of truncating variants in the 12 associated genes did not differ between European and Asian women in BCAC [31]. In CARRIERS, the associations of BARD1, RAD51C and RAD51D with ER-negative cancer were consistent with data obtained in non-Hispanic Black women, among whom ER-negative disease is more frequent; the authors emphasise stratification by tumour phenotype as a way of identifying carriers in minority populations with less access to testing [32]. In ataxia-telangiectasia, the association with gastric cancer in heterozygotes has been studied mainly in Japan, where it appears to be modulated by H. pylori infection [4].

Penetrance estimates and risk models derive mainly from populations of European ancestry; PRS313 is validated only in these populations, and the ACMG resource calls for models validated in diverse populations for RAD51C, RAD51D and BRIP1 [13, 46]. In Brazil, published data come from series of tested patients rather than population samples. In a retrospective series of 2208 breast cancer patients tested with multigene panels between 2019 and 2023, mainly from the Southeast, 9.7% had a pathogenic or likely pathogenic variant in one of 13 high- or moderate-penetrance genes (including PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D), including 5.8% in BRCA1/2; the founder TP53 NM_000546.6:c.1010G>A p.(Arg337His) (p.R337H) variant accounted for 1% of the total; prevalence of variants in non-BRCA genes did not vary significantly with age or tumour subtype; and the overall rate of variants of uncertain significance in these genes was 19.6%, a value measuring the burden of inconclusive results rather than population carrier frequency [76]. In Portugal, the familial risk clinic of the Portuguese Oncology Institute in Lisbon identified 968 families with BRCA1, BRCA2 or CHEK2 variants; among CHEK2 carriers with urological cancer, five prostate cancers and one renal cancer were recorded, all with favourable outcomes — a hospital series that cannot estimate frequency or penetrance [77]. The consulted sources contained no Portugal- or Brazil-specific penetrance estimates, nor data from other Portuguese-speaking countries, sub-Saharan Africa or the Middle East (except recurrent ATM variants in Druze and Sephardic Jews), which does not prove that studies do not exist; ancestry-specific gnomAD frequencies remain the available data for the Latin American population in general.

10. Illustrative Clinical Case

10.1 Illustrative case — a RAD51D carrier identified by cascade testing

Case constructed for teaching purposes, based on counselling scenarios in the 2025 ACMG resource. A 41-year-old nulliparous woman without a cancer history is referred because her mother was diagnosed at age 58 with high-grade serous ovarian carcinoma; testing at that time included only BRCA1 and BRCA2 and was negative. A maternal aunt had triple-negative breast cancer at age 49. Given the limited maternal test, the first step is to retrieve the DNA or repeat testing in the mother using an ovarian cancer panel; the RAD51D NM_002878.4:c.694C>T p.(Arg232Ter) variant, one of the most prevalent in this gene, was identified [13]. Predictive testing confirmed that the counsellee is heterozygous.

During counselling, it was explained that average tubo-ovarian cancer risk by age 80 is 13%, risk by age 50 is below 1%, and a family history of ovarian cancer increases risk [14, 34]. The individual CanRisk estimate, with an affected mother, gave a lifetime ovarian cancer risk above 5% and a breast cancer risk in the 17%–30% range (moderate risk). Annual mammography from age 40 was proposed, with discussion of MRI, and RRSO around age 50, earlier if vasomotor symptoms or another gynaecological indication, with examination according to the SEE-FIM protocol; ovarian surveillance was not proposed, and salpingectomy with delayed oophorectomy was presented only as a research option [13, 14]. The 38-year-old non-carrier sister had her residual breast risk calculated on the basis of the affected aunt and continued population surveillance adjusted to that calculation [13].

10.2 Published real case — CHEK2 and high PRS in early-onset male breast cancer

Tamindarov and colleagues (2026) described a 42-year-old man with a 1.8 cm left retroareolar mass; his sister had died of breast cancer at age 39 and his father had prostate cancer at age 77 [51]. Biopsy showed grade 2 invasive carcinoma of no special type, with associated ductal carcinoma in situ, strongly positive oestrogen receptor, weak progesterone receptor, HER2 1+ and Ki-67 of 28% (stage I, cT1c cN0 cM0). The 219-gene germline panel identified the pathogenic CHEK2 NM_007194.4:c.1232G>A p.(Trp411Ter) variant and a likely pathogenic MSH6 variant (NM_000179.3:c.2805del p.(Asp936IlefsTer9)); PRS313 was at centile 99. Tumour sequencing confirmed both variants without loss of heterozygosity, and the tumour was microsatellite-stable, arguing against a causal role for MSH6. The patient chose bilateral mastectomy after neoadjuvant chemotherapy with epirubicin, cyclophosphamide and paclitaxel [51]. The case illustrates three aspects of this article: the association of CHEK2 with male breast cancer and the ER-positive phenotype [3]; the additive contribution of PRS in moderate-gene carriers, proportionally greater than in BRCA1/2 carriers [48]; and the need to interpret multiple findings on an expanded panel using tumour data before assigning causality. The original open-access article includes ultrasound images of the lesion (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC13034568/figure/f1/), biopsy histology (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC13034568/figure/f2/), the patient's position in the PRS distribution generated in CanRisk (Figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC13034568/figure/f3/) and the diagnostic and treatment timeline, with tamoxifen endocrine therapy planned after surgery (Figure 4, https://pmc.ncbi.nlm.nih.gov/articles/PMC13034568/figure/f4/); the figures are not reproduced here [51]. Bilateral mastectomy was the patient's choice and does not correspond to a routine recommendation for male CHEK2 carriers, whose management follows section 7.2.

11. Prognosis and Long-Term Follow-up

Information on the prognosis of cancers associated with these genes is scarce. For CHEK2, studies differ, with some series showing poorer survival and more contralateral cancer in c.1100delC heterozygotes and others showing no difference [3]. For ATM, a series of 286 patients (eight heterozygotes) found no differences in overall survival, locoregional recurrence or disease-specific death [4]; in pancreatic cancer, patients with a germline HRR gene variant (65 with ATM) were younger, had more metastatic disease at diagnosis and longer survival [4]. For RAD51C and RAD51D, no association with breast cancer-specific survival was found [13]. Contralateral cancer risk and survival after cancer in PALB2 carriers remain open questions [10]. The Oxford Desk Reference, discussing BRCA2, notes the prognostic and predictive importance of germline status in ovarian cancer, but equivalent data are lacking for RAD51C/D or BRIP1, and ACMG calls for systematic prospective collection of treatment and survival outcomes [13, 22].

Follow-up should include: periodic reassessment of variant classification (particularly VUS and missense CHEK2 and ATM variants), usually reactively when new evidence or new family diagnoses emerge [11]; updating family history and recalculating CanRisk risk, because five- and ten-year risk changes with age and new cases [14]; reviewing surveillance exit ages according to the national programme; managing surgical menopause after RRSO, with access to a specialist clinic [14]; counselling on modifiable factors (weight, alcohol, physical activity, smoking) [11, 21]; and information that recommendations may change as data from larger cohorts emerge [13, 14]. In Europe, the relevant European Reference Network is ERN GENTURIS (genetic tumour risk syndromes), which includes hereditary breast and ovarian cancer predisposition and published the European series of biallelic CHEK2 carriers [3, 19]; among patient organisations, FORCE (Facing Hereditary Cancer Empowered) in the USA specifically serves carriers of variants in breast, ovarian and prostate cancer predisposition genes, including moderate-penetrance genes [20].

12. Summary and Final Considerations

Moderate-penetrance genes and non-BRCA ovarian susceptibility genes form a heterogeneous group that shares the damage-response and homologous recombination pathway but differs in almost every clinically consequential aspect. PALB2 approaches BRCA2 in breast risk (approximately 53% by age 80, strongly modulated by family history), adds a postmenopausal ovarian risk of approximately 5% and pancreatic risk, and is managed with surveillance equivalent to BRCA1/2. CHEK2 and ATM confer breast cancer risks of 20%–30%, predominantly ER-positive, without a relevant ovarian association; ATM adds pancreatic, prostate and gastric risk, and c.7271T>G behaves as a high-risk allele. BARD1 is associated with ER-negative and triple-negative breast cancer, not ovarian cancer. RAD51C and RAD51D are ovarian risk genes with risks of 11%–13% by age 80, with moderate breast risk involving triple-negative tumours; BRIP1 is a late-onset ovarian risk gene (approximately 6%, median age 65) without breast risk. MMR genes add earlier ovarian risk with endometrioid histology, managed within the Lynch syndrome framework.

Management converges on three principles: personalised risk estimation (CanRisk, integrating family history and, progressively, PRS, mammographic density and hormonal factors) rather than uniform gene-specific recommendations; RRSO around age 50 for RAD51C, RAD51D and BRIP1 (and PALB2 when risk warrants it), brought forward only after individual assessment given the rarity of ovarian cancer before that age; and the absence of effective ovarian screening. Differences between US (NCCN), British (UKCGG/NICE) and other national recommendations mainly reflect thresholds for access to MRI and surgery, rather than disagreement about risk data. Targeted PARP inhibitor therapy outside BRCA1/2 is currently limited to prostate cancer indications in the USA and HRD selection in ovarian cancer, with weak evidence for non-BRCA genes: in the non-BRCA subgroups of PROfound, TALAPRO-2 and AMPLITUDE, confidence intervals include no effect, and US Akeega® approval in castration-sensitive cancer (December 2025) was limited to BRCA2. The exception with consistent data is PALB2 in metastatic breast cancer (TBCRC 048, with expansion cohorts published in 2026), where olaparib remains off-label. US and European labels differ in areas with direct consequences for these carriers (olaparib monotherapy in mCRPC, HRR gene selection for talazoparib, HRD requirement for first-line niraparib), and authorisation does not equate to access in Portugal or Brazil. The genetic report should state the MANE transcript, standardised nomenclature, coverage (including CNV and pseudogene regions) and limitations, and variants of uncertain significance should not guide clinical decisions.

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