ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8168A>C (p.Asp2723Ala) (rs41293513)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218818 SCV000275234 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113879 SCV000147288 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Counsyl RCV000113879 SCV000786073 likely pathogenic Breast-ovarian cancer, familial 2 2018-02-22 criteria provided, single submitter clinical testing
GeneDx RCV000200976 SCV000210465 likely pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8168A>C at the cDNA level, p.Asp2723Ala (D2723A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant, also known as 8396A>C, has been reported in at least two individuals with familial breast cancer (Scott 2003, Gorringe 2008). Functional studies of this variant have showed decreased homology directed repair activity and increased centrosome amplification as compared to wild type (Farrugia 2008, Guidugli 2013). Farrugia et al. (2008), however, classified this variant as inconclusive based on a lack of segregation data. 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 function in vitro (Goldgar 2004, Wu 2005, Song 2014). In addition, 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 Asp2723Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, we consider BRCA2 Asp2723Ala to be a likely pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000113879 SCV000839923 likely pathogenic Breast-ovarian cancer, familial 2 2018-01-30 criteria provided, single submitter clinical testing A heterozygous c.8168A>C (p.D2723A) likely pathogenic variant in the BRCA2 gene was detected in this individual. This variant has been previously described in breast cancer (PMID: 12601471). Different missense changes at this codon, p.D2723H and p.D2723G, have been reported as pathogenic. In addition, experimental studies have shown that this variant results in reduced homology directed repair and increased centrosome amplification (PMID: 23108138, 18451181). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000045437 SCV000073450 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-01-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 2723 of the BRCA2 protein (p.Asp2723Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs41293513, ExAC 0.001%). This variant has been reported in an individual with breast cancer (PMID: 12601471). ClinVar contains an entry for this variant (Variation ID: 52516). Different missense substitutions at this codon (p.Asp2723His, p.Asp2723Gly) are reported to be pathogenic (PMID: 23108138, 21990134). This indicates that the Asp2723 residue may be important for BRCA2 protein function. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, results from homology directed repair and centrosome amplification studies are inconclusive and the impact of this missense substitution on protein function remains uncertain (PMID: 23108138, 25447315, 18451181). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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