Submissions for variant NM_000059.4(BRCA2):c.4244A>G (p.Glu1415Gly)

gnomAD frequency: 0.00001  dbSNP: rs1060502399

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471686	SCV000549542	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-03	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 1415 of the BRCA2 protein (p.Glu1415Gly). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 20960228). ClinVar contains an entry for this variant (Variation ID: 409448). 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.
GeneDx	RCV000478019	SCV000567857	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4244A>G at the cDNA level, p.Glu1415Gly (E1415G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). Using alternate nomenclature, this variant has been previously published as BRCA2 4472A>G. This variant was observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Laitman 2011). BRCA2 Glu1415Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1415Gly occurs at a position that is not conserved and is located in the BRC3 functional domain as well as the RAD51 and POLH binding domains (Cole 2011, Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Glu1415Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781078	SCV000918888	uncertain significance	not specified	2018-03-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4244A>G (p.Glu1415Gly) 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 8.4e-06 in 238704 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.4e-06 vs 7.50e-04), allowing no conclusion about variant significance. The variant, c.4244A>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Laitman 2011). 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	RCV001189703	SCV001357052	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 1415 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 with a family or personal history of breast and/or ovarian cancer (PMID: 20960228). This variant has been identified in 2/242598 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.
Ambry Genetics	RCV001189703	SCV002629780	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-08	criteria provided, single submitter	clinical testing	The p.E1415G variant (also known as c.4244A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4244. The glutamic acid at codon 1415 is replaced by glycine, an amino acid with similar properties. This alteration was detected in 1/250 high-risk Israeli women who underwent BRCA1/2 testing (Laitman Y et al. Breast Cancer Res Treat, 2011 Jun;127:489-95). Of note this alteration is also described in the literature as 4472 A to G. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001189703	SCV003848786	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003327403	SCV004034289	uncertain significance	Familial cancer of breast	2023-09-13	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 1415 of the BRCA2 protein (p.Glu1415Gly). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 20960228). ClinVar contains an entry for this variant (Variation ID: 409448). This amino acid position is not well conserved (PhyloP=0.27). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.