SRA

Identifying pathogenic missense variants in hereditary cancer is critical to the efforts of patient surveillance and risk-reduction strategies. For this purpose, many different gene panels consisting of different number and/or set of genes have been available. Particularly, the panel comprising of 26 genes that carry a varying degree of hereditary cancer risk has been extensively used. In this study, we have compiled a large collection of the missense variations reported in any of the 26 genes which are ABRAXAS1, ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2. More than a thousand of missense variants were collected from ClinVar and the targeted screen of a breast cancer cohort of 355 patients which contributed to this set with 133 novel missense variations. This collection showed a highly unbalanced distribution across 26 genes such that variations were dominantly found in the BRCA1/BRCA2 and TP53 genes while more than half of the panel genes were under-represented with less than five variations. We analyzed the impact of the missense variations on protein stability by five different predictors including both sequence- (SAAFEC and MUpro) and structure-based (Maestro, mCSM, CUPSAT) predictors. For the structure-based tools, we have utilized the AlphaFold (AF) protein structures which comprise the first structural analysis of this hereditary cancer panel. We reported a low-to-medium-level performance of the stability predictors, except from MUpro. The AUROC values ranged between 0.62-0.72 for the total set and between 0.60-0.68 for the set with high AF confidence regions. While MUpro based predictions did not show any AUROC based performance. Our results agreed with the results of the recent benchmarks that computed the power of stability predictors in discriminating the pathogenic variants. Last but not the least, our calculations relying on the AF structures revealed that the confidence score for a given position in the AF structure could alone discriminate pathogenic variants more robustly with any of the tested predictors (AUROC=0.82). Altogether, our findings represented the first structural analysis of the 26 hereditary cancer genes underscoring that (i) the thermodynamic stability predicted from AF structures is a moderate descriptor and (ii) the confidence score of AF is a strong descriptor for pathogenicity of missense variants.