ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1905T>G (p.Asp635Glu)

dbSNP: rs1555282154
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000552197 SCV000635185 uncertain significance Hereditary breast ovarian cancer syndrome 2024-07-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 635 of the BRCA2 protein (p.Asp635Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462246). 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%. 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.
Color Diagnostics, LLC DBA Color Health RCV001805161 SCV002052943 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-30 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glutamic acid at codon 635 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007905). This variant has not been identified 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.
Ambry Genetics RCV001805161 SCV002719920 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-28 criteria provided, single submitter clinical testing The p.D635E variant (also known as c.1905T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1905. The aspartic acid at codon 635 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in a cohort of 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (Djursby M et al. Front Genet, 2020 Sep;11:566266). 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.
Fulgent Genetics, Fulgent Genetics RCV002476132 SCV002785751 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3 2022-01-13 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV001805161 SCV003846376 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).
GeneDx RCV004767349 SCV005378077 uncertain significance not provided 2023-10-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 2133T>G

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