ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4213A>G (p.Ile1405Val) (rs80357353)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000679696 SCV000076503 likely benign not provided 2018-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000444773 SCV000516168 likely benign not specified 2017-03-09 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 RCV000565302 SCV000668387 likely benign Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Color RCV000565302 SCV000683163 likely benign Hereditary cancer-predisposing syndrome 2016-01-04 criteria provided, single submitter clinical testing
Counsyl RCV000031156 SCV000785577 uncertain significance Breast-ovarian cancer, familial 1 2017-09-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679696 SCV000806947 likely benign not provided 2017-10-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000444773 SCV000916735 likely benign not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change located outside of any known domain or repeat of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. In functional studies, the variant retained 75% of normal activity. This frequency is lower than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.4e-05 vs 0.001), allowing no conclusion about variant significance. The c.4213A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one recent publication reports experimental evidence evaluating an impact on protein function in a validated experimental system that measures transcriptional activation coupled to a computational algorithm with established performance characteristics. The most pronounced variant effect results in 75% of normal activity. This study reported the variant as "likely not pathogenic" in its outcome. Four 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031156 SCV000053756 benign Breast-ovarian cancer, familial 1 2011-04-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031156 SCV000145031 uncertain significance Breast-ovarian cancer, familial 1 1999-04-05 no assertion criteria provided clinical testing

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