ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4179G>A (p.Ala1393=) (rs770531115)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000411547 SCV000578736 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Ambry Genetics RCV000163821 SCV000214406 likely benign Hereditary cancer-predisposing syndrome 2015-03-23 criteria provided, single submitter clinical testing
Counsyl RCV000411547 SCV000488108 likely benign Breast-ovarian cancer, familial 2 2015-12-28 criteria provided, single submitter clinical testing
Invitae RCV000466325 SCV000560458 likely benign not provided 2019-02-06 criteria provided, single submitter clinical testing
Color RCV000163821 SCV000688857 likely benign Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000605268 SCV000694749 likely benign not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4179G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.5e-06 in 236524 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4179G>A has been reported in the literature but these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Our laboratory classified this variant as a "VUS-possibly normal" in a series of re-evaluations spanning two years (2016-2018), however, no new evidence supporting pathogenicity have been reported and at-least two other testing laboratories have classified this variant as likely benign since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV000605268 SCV000730795 benign not specified 2015-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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