ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.534A>G (p.Lys178=) (rs28897703)

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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) RCV000495740 SCV000579021 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;
GeneDx RCV000160197 SCV000210547 benign not specified 2014-09-29 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.
Ambry Genetics RCV000164085 SCV000214695 likely benign Hereditary cancer-predisposing syndrome 2015-07-24 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.
Color Health, Inc RCV000164085 SCV000683698 likely benign Hereditary cancer-predisposing syndrome 2017-02-03 criteria provided, single submitter clinical testing
Invitae RCV001082243 SCV000759331 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160197 SCV000916860 likely benign not specified 2018-02-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.534A>G alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.2e-05 in 277130 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (2.2e-05 vs 7.50e-04), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.534A>G in individuals affected with Hereditary Breast and Ovarian Cancer and has been reported. At least one publication reports experimental evidence supporting no effect on exon 7 skipping for this variant (Giacomo_2013). Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.4524G>A, p.W1508*), providing supporting evidence for a benign role. Three 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000637852 SCV001133826 likely benign not provided 2018-12-14 criteria provided, single submitter clinical testing

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