ClinVar Genomic variation as it relates to human health

This missense variant replaces alanine with proline at codon 2730 in the DNA binding/OB tower domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in significantly reduced homology-directed repair activity of the BRCA2 protein (PMID: 29884841, 33609447, 35736817). This variant has been reported in individuals affected with breast and prostate cancer (PMID: 25186627, 29398457, 32886903). This variant has been identified in 2/31394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2730 of the BRCA2 protein (p.Ala2730Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 25186627, 28888541, 31853058, 32886903; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126168). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841, 33609447). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8416G>C; This variant is associated with the following publications: (PMID: 19043619, 33609447, 31853058, 29398457, 25186627, 32377563, 35736817, 28888541, 29884841, 12228710, 35980532, 35665744, 32886903)

The BRCA2 c.8188G>C (p.Ala2730Pro) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 25186627 (2015)) and pancreatic cancer (PMIDs: 29398457 (2018), 32886903 (2020)). A functional study shows the variant has a deleterious effect on BRCA2 homology-directed repair activity (PMIDs: 29884841 (2019), 33609447 (2021), 35736817 (2022)). The frequency of this variant in the general population, 0.000072 (3/41412 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

The p.A2730P variant (also known as c.8188G>C), located in coding exon 17 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8188. The alanine at codon 2730 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). It was also identified in an individual with castration-resistant prostate cancer diagnosed at 57 whose tumor also had somatic loss of BRCA2 (VanderWeele DJ et al. Eur Urol Focus, 2018 Feb;). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). Based on internal structural analysis, this alteration introduces a large physical change that will distort a local loop motif likely impacting DNA binding ability (Ambry internal data; Yang H et al. Science, 2002 Sep;297:1837-48; Crepin T et al. Structure, 2006 Oct;14:1511-25; Shahid T et al. Nat. Struct. Mol. Biol., 2014 Nov;21:962-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Variant summary: BRCA2 c.8188G>C (p.Ala2730Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250670 control chromosomes. c.8188G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Tung_2015, Li_2019) and prostate cancer (e.g. VanderWeele_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of homology directed repair (HDR) capacity (example, Hart_2019, Richardson_2021). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG PS3) as sufficient weightage for categorization as likely pathogenic (Tavtigian_2018). Six 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 pathogenic, n=3, 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 pathogenic.