ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8168A>T (p.Asp2723Val) (rs41293513)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129267 SCV000184027 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Center for Reproductive Medicine,Shandong Provincial Hospital Affiliated to Shandong University RCV000770915 SCV000902414 pathogenic Genetic non-acquired premature ovarian failure 2018-10-01 no assertion criteria provided literature only
GeneDx RCV000216158 SCV000278878 likely pathogenic not provided 2015-11-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8168A>T at the cDNA level, p.Asp2723Val (D2723V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant has been previously published as BRCA2 8396A>T. This variant has been observed in at least two breast/ovarian cancer families (Esteban Cardenosa 2008, Meindl 2002). In support of pathogenicity, another non-conservative change at the same amino acid residue, BRCA2 Asp2723His (D2723H), has been shown to cosegregate with cancer in at least 10 families, has been identified in individuals with epithelial ovarian cancer, and was found to eliminate BRCA2 functioning in vitro (Goldgar 2004, Wu 2005, Song 2014). In addition, the other variant, BRCA2 Asp2723His, was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA2 Asp2723Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Asp2723Val occurs at a position that is fully conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider BRCA2 Asp2723Val to be a likely pathogenic variant.
Invitae RCV000205165 SCV000260419 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 2723 of the BRCA2 protein (p.Asp2723Val). The aspartic acid residue is highly 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 been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 11802209, 18060494, 22505045, 29394989), but segregation studies have not been reported. This variant is also known as c.8396A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 140975). Experimental studies have shown that this missense change disrupts the normal function of the BRCA2 protein (PMID: 29394989). Four other missense substitutions at this codon (p. Asp2723Ala, p.Asp2723His, p.Asp2723Glu, p.Asp2723Gly) have also been reported in individuals with breast and/or ovarian cancer (PMID: 12601471, 21990134, 24052750). Two of these variants, p.Asp2723His and p.Asp2723Gly, have been determined to be pathogenic (PMID: 21990134, 17924331, Invitae). This suggests that the aspartic acid residue is critical for BRCA2 function and that other missense substitutions at this position may also be pathogenic. 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.

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