Cancer predisposition genes: population carrier frequency

^* These carrier figures are approximate. Excluding specific groups (e.g. Ashkenazi Jewish), systematic testing of large population-based cohorts has not been undertaken for most of the listed genes. The accuracy of reported carrier frequency depends on how rigorous the variant curation has been in the quoted source. When considering the risk of homozygosity/compound heterozygosity in a live-born child it is important to take into account foetal/embryonic loss, the role of hypomorphic variants in recessive disease (that may be variants of uncertain significance in a dominant setting), and the lack of reliable data on carrier frequency for some genes.

^{^} While not reported, it is likely that constitutional mismatch repair deficiency (CMMRD) will be caused by inheritance of a 3′ deletion of EPCAM (that inactivates both EPCAM and MSH2) and a pathogenic variant in MSH2 (when the variants are in trans).

^# Monoallelic deletions of the 3′ end of EPCAM lead to transcriptional read-through and epigenetic silencing of MSH2 and cause Lynch syndrome (LS); biallelic inactivating variants in EPCAM cause congenital tufting enteropathy (CTE); a LS-causing 3′ deletion of EPCAM inactivates EPCAM and could be one of the variant alleles in an individual with CTE.^r

^§ In theory the combination of CTE and LS could occur in an individual with a 3′ deletion of EPCAM (that inactivates both EPCAM and MSH2) and an inactivating EPCAM variant (that does not inactivate MSH2); also, CTE and constitutional mismatch repair deficiency (CMMRD) could occur in an individual with biallelic 3′ deletion of EPCAM. To date there are no published reports of an individual with both CTE and LS/CMMRD; presumably this is in part because LS-associated cancers present at an age past the typical lifespan of CTE, and because EPCAM variants are rare.^r

^¶ Assignment of a formal Fanconi anaemia complementation group for persons with RAD51C pathogenic variants is controversial; only one consanguineous family has been reported.

 ¥ When considering the risk of homozygosity/compound heterozygosity in a live-born child it is important to take into account foetal/embryonic loss, the role of hypomorphic variants in recessive disease (that may be variants of uncertain significance in a dominant setting), and the lack of reliable data on carrier frequency for some genes.

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Bibliography

Breast Cancer Association Consortium; L. Dorling, S. Carvalho, et al. 2021. "Breast cancer risk genes - association analysis in more than 113,000 women." N Engl J Med 384(5): 428-439.

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BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

McReynolds, L.J., Y. Wang, A.S. Thompson, et al. 2020. "Population frequency of Fanconi pathway gene variants and their association with survival after hematopoietic cell transplantation for severe aplastic anemia." Biol Blood Marrow Transplant 26(5):817-822.

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Severe aplastic anemia (SAA) is most frequently immune-mediated; however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by the presence of 2 pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants, 125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplantation (HCT) (21 variants in 730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in FA genes in both groups (2.6% and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (hazard ratio, 0.85; 95% CI, 0.37 to 1.95; P = 0.71), or post-HCT cancer risk (P = 0.52). Our results demonstrate that the identification of a germline monoallelic deleterious variant in an FA gene in patients with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.

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