ClinVar Genomic variation as it relates to human health

Observed in an individual with triple negative breast cancer and a family history of breast and/or ovarian cancer (Wong-Brown et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9310G>C; This variant is associated with the following publications: (PMID: 19043619, 22228431, 12228710, 34687993, 33609447, 29884841, 27273131, 34697207, 34308104, 35665744, 35736817, 25682074)

Variant summary: BRCA2 c.9082G>C (p.Ala3028Pro) results in a non-conservative amino acid change located in the OB3 fold (IPR015188), which is part of the DNA-binding domain of the Brca2 protein (Hart_2019). Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249750 control chromosomes (gnomAD). c.9082G>C has been reported in the literature in individuals affected with breast cancer (Byers_2016, Wong-Brown_2015) and other tumor phenotypes (McReynolds_2021, Kim_2021). In addition, the variant was also reported in a patient diagnosed with late-onset Fanconi anaemia, who carried a pathogenic (frame-shift) variant in trans (Ip_2022), which suggests that the variant might be a hypomorphic allele. An in vitro functional study reported that this variant results in a decreased activity in homology-directed DNA repair (HDR) assay (Hart_2018, Richardson_2021, Hu_2022). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, partly without evidence for independent evaluation, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1), or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This missense variant replaces alanine with proline at codon 3028 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant impacts BRCA2 function in homology-directed DNA repair assays (PMID: 29884841, 33609447, 35736817). This variant has been reported in three individuals affected with breast cancer (PMID: 25682074, 27273131, ClinVar: SCV000184056.9) and in the compound heterozygous state with c.4415_4418delAGAA in an individual affected with autosomal recessive Fanconi anemia (PMID: 34687993, 34697207). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.A3028P pathogenic mutation (also known as c.9082G>C), located in coding exon 22 of the BRCA2 gene, results from a G to C substitution at nucleotide position 9082. The alanine at codon 3028 is replaced by proline, an amino acid with highly similar properties. This alteration was found to segregate with disease in a family with early-onset breast cancer (Ambry internal data). In addition, this variant has been confirmed in trans with a pathogenic mutation in BRCA2 in an individual with a mild form of Fanconi anemia (Ip E et al. J Med Genet. 2022 Sep;59(9):912-915). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet. 2021 Mar;108(3):458-468). Internal structural analysis predicts that this alteration will disrupt single-stranded DNA binding (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant has been identified in a patient with Fanconi Anemia, this alteration may be hypomorphic, and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3028 of the BRCA2 protein (p.Ala3028Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or Fanconi anemia (PMID: 25682074, 27273131, 34687993, 34697207). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 126199). 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). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

The BRCA2 c.9082G>C (p.Ala3028Pro) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25682074 (2015) and 27273131 (2016)) or Fanconi anemia with at least one case where the variant is in trans with another BRCA2 pathogenic variant (PMIDs: 34687993 (2021), 34697207 (2022), and 36721989 (2023)). Experimental studies showed that this variant has a deleterious effect in homology-directed DNA repair assays (PMIDs: 29884841 (2019), 33609447 (2021), and 35736817 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic.

At the time it was classified as a Variant of Unknown Significance.