ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3636A>G (p.Ser1212=) (rs148038877)

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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) RCV000494812 SCV000578220 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/).
GeneDx RCV000123913 SCV000167295 benign not specified 2014-02-24 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 RCV000163075 SCV000213574 likely benign Hereditary cancer-predisposing syndrome 2014-10-08 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 RCV001086581 SCV000253501 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163075 SCV000688443 likely benign Hereditary cancer-predisposing syndrome 2016-08-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123913 SCV000699048 likely benign not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.3636A>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 8.1e-06 in 246060 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3636A>G has been reported in the literature in individuals affected with breast and ovarian cancer (Judkins_2005, Anczukow_2008). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In our internal database, co-occurrence with another pathogenic variant has been reported (CHEK2 c.1368dupA, p.Glu457fsX33) for this variant, providing supporting evidence for a benign role. A functional study using minigene assay reports that it was one of the variants that did not dramatically alter splicing through disruption of an ESE (Anczukow_2008). The exact extent of functional impairment was not provided in the study. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354426 SCV001549040 uncertain significance not provided no assertion criteria provided clinical testing

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