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 We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), 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.

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“…These would include missense variants which have similar risks to truncating variants. However, there is evidence that missense variants in CHEK2 and ATM are associated with BC risk, which may be different from the risks for truncating variants 46. The models would not be applicable to carriers of such variants.…”

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“…Other putative reduced penetrance variants may be identified from Fanconi anaemia (FA)-like cases or postulated from functional assays. However, large case-control studies (e.g., [ 59 ]) are required to confirm any significant reduction in penetrance; and in the absence of such studies, individuals should be managed appropriately based on their personal and family history.…”

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“…Align Grantham Variation Grantham Deviation (Align-GVGD) [ 114 ] is a freely available, web-based tool that uses the biophysical properties of amino acids and protein multiple sequence alignments to predict where missense variations in important genes will fall on a spectrum from enriched deleterious to enriched neutral. It classifies variants according to the level of cross-species conservation observed for a single missense substitution while considering the biophysical characteristics of the amino acids, and it’s considered a non-ML method [ 114 ]. In the study by Tavtigian et al ., an extension of the Grantham difference (A-GVGD) was used to classify missense variations in the BRCA1 gene.…”