ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: BRCA2 c.506A>G (p.Lys169Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251168 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.506A>G has been reported in the literature in as a VUS in settings of somatic and germline multigene panel testing in individuals with a wide variety of cancers, example, male prostate cancer, breast cancer, the cancer genome atlas (TGCA) cohort, ALL, low-grade serous carcinomas (LGSCs) (example, Kote-Jarai_2011, Davies_2018, Lu_2015, Zhang_2015, Zhang_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA2 c.8537_8538delAG, p.Glu2846Glyfs; BRCA1 c.188T>A, p.Leu63X) and with a driver KRAS mutation, p.G12V in an individual with low-grade serous carcinomas (LGSCs) (Zhang_2021), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Biswas_2020). These results showed no damaging effect of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments and a predominant consensus towards a benign/likely benign (n=6) outcome (VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The BRCA2 c.506A>G variant is predicted to result in the amino acid substitution p.Lys169Arg. This variant has been documented in the literature as a variant of uncertain significance in individuals undergoing a wide variety of cancer testing, but no additional data supports its pathogenicity (Kote-Jarai et al. 2011. PubMed ID: 21952622; Hondow et al. 2011. PubMed ID: 21702907). In silico splicing algorithms predict this variant will create a cryptic splice junction; however functional analysis of splicing indicated it does not alter splicing (Alamut Visual Plus v.1.6.1; Table S3b, Houdayer et al. 2012. PubMed ID: 22505045; Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37941/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.