Submissions for variant NM_000059.4(BRCA2):c.10131A>C (p.Glu3377Asp)

dbSNP: rs1064793835

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482184	SCV000567148	uncertain significance	not provided	2015-07-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.10131A>C at the cDNA level, p.Glu3377Asp (E3377D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant, also known as BRCA2 10359A>C using alternate nomenclature, has been observed in 3 out of 645 women with a history of breast cancer and in 0 of 319 control subjects in single case-control study (Suter 2004). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu3377Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu3377Asp occurs at a position that is not conserved and is located within a region that interacts with RAD51 (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Glu3377Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000509753	SCV000608161	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	The p.E3377D variant (also known as c.10131A>C), located in coding exon 26 of the BRCA2 gene, results from an A to C substitution at nucleotide position 10131. The glutamic acid at codon 3377 is replaced by aspartic acid, an amino acid with highly similar properties. In one study, this alteration was observed in 3/645 breast cancer patients and absent in 342 women with benign breast disease and 319 unaffected controls of Chinese ancestry (Suter NM et al. Cancer Epidemiol. Biomarkers Prev., 2004 Feb;13:181-9). In another study, this alteration was observed in 2/7051 unselected female breast cancer patients and was also observed in 3/11241 female controls and 6/12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is poorly 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.
Invitae	RCV000698028	SCV000826668	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3377 of the BRCA2 protein (p.Glu3377Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 14973102, 30287823, 30415210). ClinVar contains an entry for this variant (Variation ID: 419387). 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.
Mendelics	RCV000698028	SCV000838916	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781053	SCV000918838	uncertain significance	not specified	2019-09-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.10131A>C (p.Glu3377Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251898 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10131A>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and in controls (Suter_2004, Momozawa_2018). These reports do 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. Five ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482184	SCV001133666	uncertain significance	not provided	2019-06-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000989095	SCV001139287	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509753	SCV004362855	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 3377 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 breast, colorectal, pancreatic, and prostate cancer case-control studies, in both cohorts, in which disease association could not be established (PMID: 14973102, 30287823, 31214711, 32980694, 33309985, 33471991). This variant has also been reported in an individual affected with ovarian cancer (PMID: 33078592). This variant has not been identified 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.
3DMed Clinical Laboratory Inc	RCV000677841	SCV000804001	uncertain significance	Cancer of the pancreas	2017-07-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355076	SCV001549846	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu3377Asp variant was identified in 5 of 15,392 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and was present in 9 of 48,100 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Suter 2004). The variant was identified in dbSNP (rs1064793835) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Integrated Genetics and 2 other submitters) and LOVD 3.0 (observed 3x). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu3377 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.