ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5342A>G (p.Asp1781Gly)

gnomAD frequency: 0.00003  dbSNP: rs80358756
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000044635 SCV000072648 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1781 of the BRCA2 protein (p.Asp1781Gly). This variant is present in population databases (rs80358756, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 12491487). ClinVar contains an entry for this variant (Variation ID: 51840). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33293522). 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 RCV000214135 SCV000277720 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-15 criteria provided, single submitter clinical testing The p.D1781G variant (also known as c.5342A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5342. The aspartic acid at codon 1781 is replaced by glycine, an amino acid with similar properties. This alteration behaved like known benign variants in a mouse embryonic stem cell survival and drug sensitivity assay, however these assays are not validated for variants outside the BRCA2 DNA Binding Domain (Biswas K et al. NPJ Genom Med, 2020 Dec;5:52). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001753457 SCV002007548 uncertain significance not provided 2022-05-25 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with endometrial cancer (Lu 2015); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5570A>G; This variant is associated with the following publications: (PMID: 31131967, 10923033, 12491487, 26689913)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001753457 SCV002774487 uncertain significance not provided 2021-06-16 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000214135 SCV003847174 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Myriad Genetics, Inc. RCV000113420 SCV004043185 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2023-07-13 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health RCV000113420 SCV004846560 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 1781 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in mouse embryonic stem cells has shown this variant does not impact function in cell survival or drug sensitivity assays (PMID: 33293522). This variant has been reported in an individual affected with breast cancer (PMID: 12491487). This variant has been identified in 3/282100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113420 SCV000146597 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing

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