Submissions for variant NM_000059.4(BRCA2):c.7630G>C (p.Gly2544Arg)

dbSNP: rs587781485

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225896	SCV000283319	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2544 of the BRCA2 protein (p.Gly2544Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast cancer (PMID: 30159786). ClinVar contains an entry for this variant (Variation ID: 236907). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. 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	RCV000580094	SCV000683897	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2544 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast cancer (PMID: 30159786). 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	RCV000580094	SCV001189071	likely benign	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199884	SCV001370637	uncertain significance	not specified	2020-05-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7630G>C (p.Gly2544Arg) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7630G>C has been reported in the literature in one individual with personal or family history of breast cancer (de Souza Timoteo_2018). The report does 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001199884	SCV002070684	uncertain significance	not specified	2019-05-09	criteria provided, single submitter	clinical testing
GeneDx	RCV003235150	SCV003933343	uncertain significance	not provided	2023-05-26	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; Observed in an individual with a personal and/or family history of breast cancer (de Souza Timoteo et al., 2018); Also known as 7858G>C; This variant is associated with the following publications: (PMID: 12228710, 30159786, 29884841, 32377563, 28704513, 29881398)
All of Us Research Program, National Institutes of Health	RCV003998701	SCV004844447	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2544 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast cancer (PMID: 30159786). 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.