Submissions for variant NM_000059.4(BRCA2):c.4478A>G (p.Glu1493Gly)

gnomAD frequency: 0.00001  dbSNP: rs80358679

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218014	SCV000279275	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4478A>G at the cDNA level, p.Glu1493Gly (E1493G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 4706A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu1493Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1493Gly occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (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 Glu1493Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509781	SCV000607938	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-04	criteria provided, single submitter	clinical testing	The p.E1493G variant (also known as c.4478A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4478. The glutamic acid at codon 1493 is replaced by glycine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556739	SCV000635370	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-18	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 1493 of the BRCA2 protein (p.Glu1493Gly). This variant is present in population databases (rs80358679, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 126045). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218014	SCV000889048	uncertain significance	not provided	2019-07-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763887	SCV000894822	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
Color Diagnostics, LLC DBA Color Health	RCV000509781	SCV001348074	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553670	SCV001774611	uncertain significance	not specified	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4478A>G (p.Glu1493Gly) 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 5.6e-06 in 357318 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4478A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509781	SCV003850539	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).
Myriad Genetics, Inc.	RCV000113308	SCV004043186	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113308	SCV000146432	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732684	SCV005348740	uncertain significance	BRCA2-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The BRCA2 c.4478A>G variant is predicted to result in the amino acid substitution p.Glu1493Gly. This variant was reported in a control and not in affected individuals in a breast cancer case-control study (Breast Cancer Association Consortium. 2021. PubMed ID: 33471991). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to benign (http://www.ncbi.nlm.nih.gov/clinvar/variation/126045). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.