ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3330A>C (p.Glu1110Asp)

gnomAD frequency: 0.00001  dbSNP: rs369294255
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580365 SCV000683548 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-31 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 1110 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 detected in a breast cancer case-control meta-analysis in 3/60463 cases and 4/53457 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000593). This variant has been identified in 3/268366 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758882 SCV000887788 uncertain significance not provided 2024-03-25 criteria provided, single submitter clinical testing The BRCA2 c.3330A>C (p.Glu1110Asp) variant has been observed in several individuals with breast cancer and in reportedly healthy individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). In addition, this variant has been reported to co-occur with a BRCA2 pathogenic variant in an individual with ovarian cancer, suggesting this variant was not the primary cause of disease (PMID: 33526602 (2021)). The frequency of this variant in the general population, 0.00015 (3/19484 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000816307 SCV000956808 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-22 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 1110 of the BRCA2 protein (p.Glu1110Asp). This variant is present in population databases (rs369294255, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 252827). 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 RCV000580365 SCV001181430 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-25 criteria provided, single submitter clinical testing The p.E1110D variant (also known as c.3330A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3330. The glutamic acid at codon 1110 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260303 SCV001437225 uncertain significance not specified 2020-09-08 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3330A>C (p.Glu1110Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 236968 control chromosomes (gnomAD). 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.3330A>C in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4 RCV000580365 SCV002533785 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-03 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000580365 SCV003851869 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).
Sharing Clinical Reports Project (SCRP) RCV000239030 SCV000297430 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2010-12-22 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000758882 SCV001931784 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000758882 SCV001951337 likely benign not provided no assertion criteria provided clinical testing

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