ClinVar Genomic variation as it relates to human health

The BRCA2 c.116C>T; p.Ala39Val variant (rs398122724) is reported in the literature in an individual affected with breast and thyroid cancer who also carried a pathogenic variant in CHEK2 (Dominguez-Valentin 2018). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 39 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Ala39Val variant is uncertain at this time.

In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The variant has also been reported in an individual with Cowden like syndrome (PMID: 28608266 (2017)). In addition, functional studies have shown that this variant does not affect BRCA2 splicing and protein expression (PMID: 35979650 (2022)). However additional studies are required to assess other BRCA2 protein functions. The frequency of this variant in the general population, 0.000004 (1/251240 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28608266, 31131967)

This missense variant replaces alanine with valine at codon 39 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). RNA studies using a minigene assay and patient-derived RNA have shown that this variant does not impact splicing (PMID: 28608266, 35979650). A functional study has reported that this variant does not impact BRCA2 function in the complementation of Brca2-deficient mouse embryonic stem cells and in a homology-directed DNA repair assay (PMID: 35979650). This variant has been reported in an individual affected with bilateral breast cancer, this individual also carried a pathogenic variant in the CHEK2 gene that could explain the observed phenotype (PMID: 28608266). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 5/60466 cases and 3/53461 unaffected controls, showing inconclusive association with disease (OR=1.474, 95%CI 0.352 to 6.167, p-value=0.731) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007683). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces alanine with valine at codon 39 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with bilateral breast cancer, this individual also carried a pathogenic variant in the CHEK2 gene that could explain the observed phenotype (PMID: 28608266). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 5/60466 cases and 3/53461 controls, showing inconclusive association with disease (OR=1.474, 95%CI 0.352 to 6.167, p-value=0.731) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007683). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.A39V variant (also known as c.116C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 116. The alanine at codon 39 is replaced by valine, an amino acid with similar properties. This alteration has been reported in one Norwegian family with multiple early-onset cancers (Dominguez-Valentin M et al. Fam. Cancer. 2018 Jan;17:141-153). This alteration was also cited as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 09;40(9):1557-1578). This amino acid position is highly 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.