Submissions for variant NM_000059.4(BRCA2):c.2245A>G (p.Ser749Gly)

dbSNP: rs80358495

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043961	SCV000071974	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 749 of the BRCA2 protein (p.Ser749Gly). This variant is present in population databases (rs80358495, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and gastric cancer (PMID: 25348012, 26689913, 32426482). ClinVar contains an entry for this variant (Variation ID: 51259). 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.
Ambry Genetics	RCV000129533	SCV000184310	likely benign	Hereditary cancer-predisposing syndrome	2024-10-17	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	RCV000481492	SCV000564769	uncertain significance	not provided	2022-08-29	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; Also known as 2473A>G; This variant is associated with the following publications: (PMID: 26689913, 25348012, 10923033, 32426482)
Color Diagnostics, LLC DBA Color Health	RCV000129533	SCV001339316	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 749 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 performed for this variant. This variant has been reported individuals affected with breast cancer (PMID: 33113089, 33471991; Leiden Open Variation Database DB-ID BRCA2_001704) and in individuals affected with stomach adenocarcinoma or gastric cancer (PMID: 26689913, 32426482). This variant has been identified in 1/251286 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	RCV001193201	SCV001361903	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2245A>G (p.Ser749Gly) 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 4e-06 in 251286 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2245A>G has been reported in the literature in individuals affected with gastric cancer and breast cancer (examples: Lu_2015, Suzuki_2020, Lattimore_2021). These reports however 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: 26689913, 33113089, 32426482). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=6; Likely benign: n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV001193201	SCV002517971	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477144	SCV002785236	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	2022-03-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129533	SCV003846600	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).
PreventionGenetics, part of Exact Sciences	RCV004537190	SCV004115472	uncertain significance	BRCA2-related disorder	2023-06-05	criteria provided, single submitter	clinical testing	The BRCA2 c.2245A>G variant is predicted to result in the amino acid substitution p.Ser749Gly. This variant (also known as 2473A>G) was reported in individuals with a history of gastric and breast cancers (Suzuki et al 2020. PubMed ID: 32426482; Supplementary Table 3, Lattimore et al. 2020. PubMed ID: 33113089; Supplementary Data 14, Lu et al. 2015. PubMed ID: 26689913). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32910737-A-G). In ClinVar, this variant has conflicting interpretations, ranging from 'likely benign' to 'uncertain' (https://www.ncbi.nlm.nih.gov/clinvar/variation/51259/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000113026	SCV004847028	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 749 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 performed for this variant. This variant has been reported individuals affected with breast cancer (PMID: 33113089, 33471991; Leiden Open Variation Database DB-ID BRCA2_001704) and in individuals affected with stomach adenocarcinoma or gastric cancer (PMID: 26689913, 32426482). This variant has been identified in 1/251286 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113026	SCV000146020	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000481492	SCV001955472	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000481492	SCV001969485	likely benign	not provided		no assertion criteria provided	clinical testing