ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4111G>C (p.Gly1371Arg) (rs774593602)

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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 RCV000165223 SCV000215937 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000688766 SCV000816390 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-07-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1371 of the BRCA1 protein (p.Gly1371Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 185744). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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 RCV000165223 SCV000906470 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779865 SCV000916734 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4111G>C (p.Gly1371Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 243394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4111G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010). 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. One clinical diagnostic laboratory has 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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