ClinVar Miner

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

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Total submissions: 6
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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 2016-10-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586512 SCV000694842 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5210A>T (p.Asp1737Val) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 119792 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance, without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000699007 SCV000827699 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-11 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.
ITMI RCV000120322 SCV000084474 not provided not specified 2013-09-19 no assertion provided reference population

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