Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Abstract

BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS The most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS These results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants inATM,BRCA1,BRCA2,CHEK2, andPALB2

“…Loss-of-function variants and pathogenic or likely pathogenic variants in the ClinVar database were classified as PVs. Since missense and lowpenetrance variants in CHEK2 have a lower risk of breast cancer than truncating variants, 12,13 these were excluded from the primary analysis. CBC risks associated with missense variants and the low penetrance CHEK2 p.Ile157Thr (c.470T.C) variant were evaluated separately.…”

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

“…The evidence from functional studies may often be controversial and systematic case-control comparisons to assess the pathogenicity are not conclusive if the allele frequency in the general population is ultra-low. For CHEK2, several rare missense variants have been reported and generally these have been estimated to confer lower breast cancer risk than protein truncating variants [15]. However, it is possible that rare missense variants in the evolutionarily conserved functional sites cause higher cancer risk [16] and risk estimations for individual alleles are needed.…”