ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.7928C>G (p.Ala2643Gly) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251292 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7928C>G has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Lu_2012, Thery_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA2 c.2309C>A, p.Ser770*), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Farrugia_2008, Mesman_2018). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=4; 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 likely benign.

Observed in individuals with personal and/or family history of breast, ovarian, or pancreatic cancer, but also observed in unaffected controls (Thry et al., 2011; Lu et al., 2012; Shimelis et al., 2017; Mesman et al., 2018; Machackova et al., 2019; Wong et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8156C>G; This variant is associated with the following publications: (PMID: 22505045, 25447315, 24323938, 18451181, 23893897, 28283652, 26913838, 30212499, 22476429, 21673748, 19043619, 29988080, 31131967, 31469826, 31409081, 34597585, 25348012, 12228710)

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.

The p.Ala2643Gly variant was identified as neutral in a functional assay assessing the ability of the variant to repair DNA damage by homologous recombination, and control of centriole amplification (Farrugia 2008). Another functional assay assessing splicing effects using a reporter minigene found no splicing defect and patient RNA behaved as wildtype (Thery 2011). The variant was also found to be neutral using a computational method using probabilistic likelihood ratios, predicting protein function impairment (Karchin 2008). The variant was identified in dbSNP (ID: rs80359018) “With unknown pathogenicity”, but no frequency information was provided; NHLBI Exome Sequencing Project (Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001); the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 3 of 121376 chromosomes (frequency: 0.000025) (OR 3 individuals from a population of European (Non-Finnish) individuals and none from East Asian, Other, African, Latino, South Asian, or European (Finnish) individuals); Clinvitae database (3x), the ClinVar database (unclassified due to conflicting interpretations, with likely benign by the Sharing Clinical Reports Project, derived from Myriad reports, and Ambry Genetics; as uncertain significance by BIC, and classification not provided by Invitae), the BIC database (3X with unknown clinical importance and pending classification), and UMD (unavailable). The p.Ala2643 residue was conserved in mammals but not other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Two of 5 in-silico splicing software tools (NNSPLICE, GeneSplicer, Human Splicing Finder, MaxEntScan, SpliceSiteFinder-like) predict creation of a 5' splicing site, although this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time; this variant is classified as a variant of unknown significance.