Submissions for variant NM_000059.4(BRCA2):c.9530A>G (p.Glu3177Gly)

gnomAD frequency: 0.00001  dbSNP: rs876658365

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222361	SCV000273483	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-25	criteria provided, single submitter	clinical testing	The p.E3177G variant (also known as c.9530A>G), located in coding exon 25 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9530. The glutamic acid at codon 3177 is replaced by glycine, an amino acid with similar properties. In one study, this variant was seen in 1/431 unrelated breast cancer families (Velasco E et al. Electrophoresis. 2005 Jun;26(13):2539-52). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550708	SCV000635749	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3177 of the BRCA2 protein (p.Glu3177Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with cancer (PMID: 15937982, 32522261). This variant is also known as 9758A>G. ClinVar contains an entry for this variant (Variation ID: 230066). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758978	SCV000887967	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual with breast cancer as a variant of uncertain significance (PMID:15937982 (2005)). This variant has also been reported in a large hereditary cancer screening study (PMID: 31853058 (2020)). The frequency of this variant in the general population, 0.000008 (2/251358 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000765144	SCV000896370	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	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780013	SCV000917006	uncertain significance	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9530A>G (p.Glu3177Gly) results in a non-conservative amino acid change located in the BRCA2 OB3 domain (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246134 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.1e-06 vs 7.50e-04), allowing no conclusion about variant significance. The variant, c.9530A>G, has been reported in the literature in individuals affected or with family history of Hereditary Breast and Ovarian Cancer (Velasco_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000222361	SCV001733841	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 3177 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 detected in an individual affected with breast cancer and in a family suspected of being affected with hereditary breast and ovarian cancer (PMID: 15937982; Color internal data). This variant has been identified in 2/251358 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.
Sema4, Sema4	RCV000222361	SCV002532044	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation
GeneDx	RCV000758978	SCV002770072	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	Observed in individuals with personal and/or family history of breast, ovarian, colorectal, or other cancer (Velasco et al., 2005; Li et al., 2020; Velzquez et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9758A>G; This variant is associated with the following publications: (PMID: 12228710, 32522261, 31853058, 32377563, 29884841, 31911673, 15937982)
All of Us Research Program, National Institutes of Health	RCV000239286	SCV004846185	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 3177 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 detected in an individual affected with breast cancer and in a family suspected of being affected with hereditary breast and ovarian cancer (PMID: 15937982; Color internal data). This variant has been identified in 2/251358 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000239286	SCV005402407	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-04-12	criteria provided, single submitter	clinical testing	The BRCA2 c.9530A>G (p.Glu3177Gly) missense change has a maximum subpopulation allele frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function but this prediction has not been confirmed by functional studies. This variant has been reported in a breast cancer family (PMID:15937982). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000239286	SCV000297580	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-02-02	no assertion criteria provided	clinical testing