ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2813C>A (p.Ala938Glu) (rs55773834)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044067 SCV000072080 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 938 of the BRCA2 protein (p.Ala938Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs55773834, ExAC 0.04%). This variant has been reported in an individual affected with glioblastoma (PMID: 26689913) and in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51353). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000130944 SCV000185857 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Michigan Medical Genetics Laboratories,University of Michigan RCV000083094 SCV000267755 uncertain significance Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000587088 SCV000278842 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2813C>A at the cDNA level, p.Ala938Glu (A938E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 3041C>A. This variant has been identified in the tumor and germline of an individual with glioblastoma (Lu 2015). BRCA2 Ala938Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located within a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ala938Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000083094 SCV000296743 uncertain significance Breast-ovarian cancer, familial 2 2016-05-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587088 SCV000694633 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2813C>A (p.Ala938Glu) variant involves the alteration of a non-conserved nucleotide. The variant is located outside of any know functional domain or repeat and 3/5 in silico tools predict a benign outcome for this variant. The variant is present in the large control population datasets of ExAC and gnomAD at a frequency 0.000036 (4/120732 and 10/276740 chrs tested), exclusively in individuals of African descent ( 0.0004; 4/10194 and 10/23994 chrs tested, respectively). Although observed frequency does not exceed the estimated maximal expected allele frequency of a pathogenic variant in this gene (0.00075) the variant may represent a rare ethnic-specific functional polymorphism.The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-Possibly Benign until additional evidence becomes available.
Counsyl RCV000083094 SCV000785779 uncertain significance Breast-ovarian cancer, familial 2 2017-11-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587088 SCV000889011 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing
Color RCV000130944 SCV000903800 likely benign Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083094 SCV000115168 uncertain significance Breast-ovarian cancer, familial 2 2008-01-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083094 SCV000146120 uncertain significance Breast-ovarian cancer, familial 2 2003-10-29 no assertion criteria provided clinical testing

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