ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2862A>G (p.Leu954=) (rs559190752)

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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) RCV000495716 SCV000578214 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;
Ambry Genetics RCV000163996 SCV000214598 likely benign Hereditary cancer-predisposing syndrome 2014-11-10 criteria provided, single submitter clinical testing
Invitae RCV000588743 SCV000261814 likely benign not provided 2019-02-18 criteria provided, single submitter clinical testing
GeneDx RCV000419724 SCV000527309 likely benign not specified 2017-12-28 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000419724 SCV000591413 likely benign not specified 2014-06-02 criteria provided, single submitter clinical testing
Color RCV000163996 SCV000688405 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588743 SCV000698982 likely benign not provided 2017-04-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2862A>G (p.Leu954Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant does not affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.000033 (4/121352 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). A study on colonic cancer found the variant in a colonic adenoma sample. However, there was at least one pathogenic co-occurrence of a possible driver mutation in the APC gene (p.Arg1450X; Pathogenic/likely pathogenic in ClinVar), suggesting that this variant of interest is not likely to be involved in this oncogenesis and its presence in the adenoma sample could represent a passenger mutation (Dame_bioRxiv_2017). Another publication included the variant as part of a common haplotype and classified it as a benign polymorphism (Judkins_Cancer Res_2005). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign. Taken together, this variant is classified as Likely Benign until unequivocal evidence of germline co-occurrence with other pathogenic variants, and/or functional and control evidence supportive of a benign role are obtained.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588743 SCV000888873 likely benign not provided 2019-08-18 criteria provided, single submitter clinical testing

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