ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5210A>T (p.Asp1737Val) (rs587778120)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586512 SCV000210347 uncertain significance not provided 2016-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5210A>T at the cDNA level, p.Asp1737Val (D1737V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature this variant would be defined as BRCA2 5438A>T. This variant was identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. BRCA2 Asp1737Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp1737Val occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider BRCA2 Asp1737Val to be a variant of uncertain significance.
Counsyl RCV000410599 SCV000488133 uncertain significance Breast-ovarian cancer, familial 2 2016-01-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571871 SCV000661373 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000120322 SCV000694842 uncertain significance not specified 2020-08-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5210A>T (p.Asp1737Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 248142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5210A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Experimental evidence indicated the variant to confer normal function (Ikegami_2020). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until further evidence of clinical or functional importance becomes available.
Invitae RCV000699007 SCV000827699 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1737 of the BRCA2 protein (p.Asp1737Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 133729). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000571871 SCV001343953 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
ITMI RCV000120322 SCV000084474 not provided not specified 2013-09-19 no assertion provided reference population

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