ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8169T>A (p.Asp2723Glu) (rs1060502432)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467822 SCV000549619 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 2723 of the BRCA2 protein (p.Asp2723Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 409493). 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, but these predictions have not been confirmed by published functional studies. Variants that disrupt the p.Asp2723 amino acid residue in BRCA2 have been observed in affected individuals (PMID: 15290653, 16489001, 11207042, 23961350, 24728189, 25452441). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Ambry Genetics RCV000568974 SCV000666072 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing The p.D2723E variant (also known as c.8169T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8169. The aspartic acid at codon 2723 is replaced by glutamic acid, an amino acid with highly similar properties. While this exact alteration has not been reported in the literature to date, other amino acid substitutions at this codon (p.D2723G and p.D2723H) have been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). In one functional study, three different alterations(p.D2723H/G/A) at this position were shown to be deleterious to the function of the protein using a homology-directed DNA break repair (HDR) functional assay (Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75). In another functional study, two different alterations(p.D2723H/G) at this position were shown to be inactivating the function of the protein using centrosome amplification assay and HDR assay (Farrugia DJ et al. Cancer Res. 2008 May; 68(9):3523-31). The p.D2723E variant occurs in a structural hotspot region of the protein and is predicted to destabilize the protein and disrupt the native protein-protein (BRCA2-DSS1) interaction (Yang et al. Science. 2002; 297(5588):1837-48; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000568974 SCV000910281 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194439 SCV001364000 uncertain significance not specified 2019-03-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8169T>A (p.Asp2723Glu) results in a conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245866 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.8169T>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as likely pathogenic and once as uncertain significance. In addition, missense variants affecting the same codon, Asp2723Ala, Asp2723Gly, Asp2723His, Asp2723Val, have been reported in association with Breast cancer, therefore, suggesting Asp could play a key role in protein function. However, based on the evidence outlined above, the variant was classified as uncertain significance.

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