ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4578A>G (p.Thr1526=) (rs202022822)

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Total submissions: 8
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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) RCV000495149 SCV000578012 benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; and frequency 0.0024 (East Asian), derived from ExAC (2014-12-17).
Ambry Genetics RCV000163588 SCV000214148 likely benign Hereditary cancer-predisposing syndrome 2014-07-03 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001084558 SCV000261061 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240740 SCV000265953 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
GeneDx RCV000427408 SCV000515708 likely benign not specified 2017-12-11 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000427408 SCV000591910 benign not specified 2012-10-01 criteria provided, single submitter clinical testing
Color RCV000163588 SCV000683631 likely benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588843 SCV000694783 likely benign not provided 2017-01-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4578A>G (p.Thr1526Thr) variant causes a synonymous change involving a non-conserved nucleotide, 2/5 programs in Alamut predict that this variant may generate a novel 3' splicing acceptor site, one program also predicts the wild-type allele of this variant may generate the same 3' splicing acceptor site, suggesting this predicted effect is unlikely associated with the disease. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 19/120502 (1/6369), predominantly in the East Asian cohort, 19/8642 (1/454), which exceeds the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/3333. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. Multiple publications have cited the variant in affected individuals, however, with limited available information (ie, lack of co-occurrence and cosegregation data). Multiple clinical diagnostic laboratories/reputable databases have classified the variant from "uncertain significance" to "likely benign/benign." Therefore, the variant of interest has been classified as "Likely Benign."

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