Submissions for variant NM_000059.4(BRCA2):c.5813G>C (p.Gly1938Ala)

gnomAD frequency: 0.00002  dbSNP: rs41293499

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129261	SCV000184021	likely benign	Hereditary cancer-predisposing syndrome	2024-11-26	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.
GeneDx	RCV000657051	SCV000279422	uncertain significance	not provided	2024-02-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6041G>C; This variant is associated with the following publications: (PMID: 33850299, 29884841, 32377563, 33939675, 33471991, 31853058)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257904	SCV000549550	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129261	SCV000911399	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 1938 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 a hematological malignancy (PMID: 33850299). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008371). This variant has been identified in 4/250812 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168583	SCV000918976	uncertain significance	not specified	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5813G>C (p.Gly1938Ala) 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 allele was found at a frequency of 1.6e-05 in 250812 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5813G>C has been reported in the literature in individuals affected with Breast cancer (Dorling_2021), Hematological cancer (Singhal_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six Clinvar submitters have assessed the variant since 2014: five classify the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798275	SCV002043254	uncertain significance	Breast and/or ovarian cancer	2021-02-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168583	SCV002065640	uncertain significance	not specified	2018-09-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129261	SCV003850696	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657051	SCV004220473	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113428 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant was found both in individuals with breast cancer as well as healthy individuals in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000076942	SCV004846652	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 1938 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 a hematological malignancy (PMID: 33850299). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008371). This variant has been identified in 4/250812 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.
Sharing Clinical Reports Project (SCRP)	RCV000076942	SCV000108739	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657051	SCV000592003	likely benign	not provided		no assertion criteria provided	clinical testing	The p.Gly1938Ala variant was not identified in the literature but was identified in dbSNP (ID:rs41293499 ) “With probable-non-pathogenic allele”. The p.Gly1938Ala variant was classified as a likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Gly1938 residue is not conserved in mammals and the variant amino acid alanine (Ala) is present in opossum, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
PreventionGenetics, part of Exact Sciences	RCV004732647	SCV005366067	uncertain significance	BRCA2-related disorder	2024-08-04	no assertion criteria provided	clinical testing	The BRCA2 c.5813G>C variant is predicted to result in the amino acid substitution p.Gly1938Ala. This variant was reported in an individual with a haematological malignancy, an individual with breast cancer, and a healthy control individual (Singhal et al 2021. PubMed ID: 33850299; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/91425/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.