ClinVar Genomic variation as it relates to human health

Observed in individuals with melanoma, breast, ovarian, or pancreatic cancers, one of whom also carried a pathogenic BRCA2 variant however phase was unknown (Bartsch 2010, Sanz 2010, Azzollini 2016, Caleca 2018, Santonocito 2020, Wai 2020); Published functional studies demonstrate no damaging effect: similar to wild type in homologous recombination and double-strand break repair (HR/DSBR) activity, inhibition of HR/DSBR activity with over-expression, PALB2 binding activity, and nuclear localization (Xia 2006, Caleca 2018); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing, however splicing studies demonstrate mixed results (Pettigrew 2008, Sanz 2010, Tubeuf 2020); Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 307A>G; This variant is associated with the following publications: (PMID: 32438681, 24323938, 20041885, 17899372, 27062684, 32123317, 30410870, 16793542, 32641407, 20215541)

Variant summary: BRCA2 c.79A>G (p.Ile27Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.79A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (example, Houdayer_2012, Bartsch_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.631G>A p.Val211Ile and c.7008-2A>T in one patient with Ovarian Cancer), providing supporting evidence for a benign role (Santonocito_2020). Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant using mESC complementation and HDR assay (example, Xia_2006, Caleca_2018, Thomassen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 20041885, 24323938, 22505045, 19609323, 17899372, 32438681, 20215541, 35979650, 16793542). ClinVar contains an entry for this variant (Variation ID: 52467). Based on the evidence outlined above, the variant was classified as likely benign.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the BRCA2 protein (p.Ile27Val). This variant is present in population databases (rs80359034, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of melanoma, pancreatic, breast and/or ovarian cancer (PMID: 20041885, 27062684, 32438681). This variant is also known as 307A>G. ClinVar contains an entry for this variant (Variation ID: 52467). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 16793542, 24323938, 32641407). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.I27V variant (also known as c.79A>G), located in coding exon 2 of the BRCA2 gene, results from an A to G substitution at nucleotide position 79. The isoleucine at codon 27 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a proband diagnosed with melanoma whose father had pancreatic cancer; both the proband and his father carried the alteration, as did an unaffected uncle (Bartsch DK et al. Clin Genet. 2010 Apr; 77(4):333-41). Authors reported that it was unclear if this alteration was linked with disease. This alteration was also reported in multiple individuals diagnosed with breast and/or ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Santonocito C et al. Cancers (Basel), 2020 May;12:). One study looked at exonic splicing enhancers using an in silico model to predict which variants may affect splicing and this alteration was predicted to have an increased effect on exonic splicing enhancers; authors reported this may adversely affect splicing but further functional studies are needed (Pettigrew CA et al. Breast Cancer Res Treat. 2008 Jul; 110(2):227-34). In another study, this alteration had activity similar to wildtype in a PALB2 binding assay and a homologous recombination assay (Xia B et al. Mol Cell. 2006 Jun; 22(6):719-29). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).