ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10131A>C (p.Glu3377Asp) (rs1064793835)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677841 SCV000804001 uncertain significance Cancer of the pancreas 2017-07-29 no assertion criteria provided clinical testing
Ambry Genetics RCV000509753 SCV000608161 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-18 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000781053 SCV000918838 uncertain significance not specified 2018-10-04 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 246668 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 (Suter_2004). 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000698028 SCV000826668 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 3377 of the BRCA2 protein (p.Glu3377Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with breast cancer (PMID: 14973102). ClinVar contains an entry for this variant (Variation ID: 419387). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Mendelics RCV000698028 SCV000838916 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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