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

dbSNP: rs1555282154

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001013576	SCV001174183	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	The p.D635E variant (also known as c.1905T>A), located in coding exon 9 of the BRCA2 gene, results from a T to A 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 observed in 0/7,051 unselected female breast cancer patients and was observed in 3/11,241 female controls of Japanese ancestry. In addition, it was observed in 1/53 unselected male breast cancer patients and in 1/12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). This alteration was detected in a study of 11,386 Chinese Han individuals over 19 years of age without history of cancer undergoing routine health examinations (Dong H et al. J Med Genet, 2021 Aug;58:565-569). This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001326443	SCV001517474	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-02	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: 820280). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV001013576	SCV002053084	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-15	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 an individual affected with breast cancer (PMID: 30287823) but also in healthy control individuals (PMID: 30287823, 32980694). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) but has been reported in a population study in Macau (PMID: 32817299). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001013576	SCV003846377	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).