ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.564A>G (p.Glu188=) (rs768065826)

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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) RCV000495344 SCV000578436 likely benign Breast-ovarian cancer, familial 1 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; http://priors.hci.utah.edu/PRIORS/).
Ambry Genetics RCV000163489 SCV000214046 likely benign Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
Invitae RCV000471193 SCV000560225 likely benign Hereditary breast and ovarian cancer syndrome 2017-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000481620 SCV000570709 uncertain significance not provided 2018-03-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.564A>G at the DNA level. It is silent at the coding level, preserving a Glutamic Acid at codon 188. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging. Using alternate nomenclature, this variant would be defined as BRCA1 683A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.564A>G was observed at an allele frequency of 0.007% (8/111646 alleles) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA1 c.564A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481620 SCV000888955 likely benign not provided 2017-12-06 criteria provided, single submitter clinical testing
Color RCV000163489 SCV000911783 likely benign Hereditary cancer-predisposing syndrome 2016-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779908 SCV000916818 likely benign not specified 2019-08-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.564A>G 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 3.2e-05 in 251252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.564A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. This variant was found in one healthy older woman in a reputed germline gnomic database (FLOSSIES). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x VUS, 5x Likely benign). Based on the evidence outlined above, the variant was classified as likely benign.

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