Submissions for variant NM_000059.4(BRCA2):c.710A>G (p.Asp237Gly)

dbSNP: rs730881506

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160029	SCV000210253	uncertain significance	not provided	2024-04-09	criteria provided, single submitter	clinical testing	Observed in individuals with BRCA2-related cancers (PMID: 29161300, 35127508, 36775216); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 938A>G; This variant is associated with the following publications: (PMID: 32467295, 31131967, 29161300, 33471991, 35127508, 29884841, 32377563, 31853058, 36775216)
Ambry Genetics	RCV000222640	SCV000275255	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	The p.D237G variant (also known as c.710A>G), located in coding exon 8 of the BRCA2 gene, results from an A to G substitution at nucleotide position 710. The aspartic acid at codon 237 is replaced by glycine, an amino acid with similar properties. This variant has been reported in a Brazilian HBOC cohort (Alemar B et al. PLoS ONE, 2017 Nov;12:e0187630). 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	RCV000637701	SCV000759172	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-14	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 237 of the BRCA2 protein (p.Asp237Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29161300). ClinVar contains an entry for this variant (Variation ID: 182180). 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	RCV000222640	SCV000911744	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 237 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 individuals with a personal or family history of breast and/or ovarian cancer (PMID: 29161300, 35127508, Color internal data) and in 2 healthy controls (Leiden Open Variation Database DB-ID BRCA2_007745; PMID: 33471991). This variant has been reported in a suspected hereditary breast and ovarian cancer family with co-occurrence and family history likelihood ratios of 1.0246 and 0.492, respectively (PMID: 31131967). 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.
All of Us Research Program, National Institutes of Health	RCV004804688	SCV005424261	uncertain significance	BRCA2-related cancer predisposition	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 237 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 observed in at least one individual affected with or at-risk for breast or ovarian cancer (PMID: 29161300) and has been reported in a suspected hereditary breast and ovarian cancer family with co-occurrence and family history likelihood ratios of 1.0246 and 0.492, respectively (PMID: 31131967). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055647	SCV005725552	uncertain significance	not specified	2024-11-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.710A>G (p.Asp237Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250416 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.710A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Andreis_2023, Alemar_2017, Andrikopoulou_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29161300, 36775216, 35127508). ClinVar contains an entry for this variant (Variation ID: 182180). Based on the evidence outlined above, the variant was classified as uncertain significance.