ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2043T>G (p.Ser681Arg) (rs143920945)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214049 SCV000273512 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000542308 SCV000635826 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-17 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 681 of the BRCA1 protein (p.Ser681Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 230089). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000214049 SCV000909355 likely benign Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779863 SCV000916732 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2043T>G (p.Ser681Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2043T>G has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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