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 The p.G1371R variant (also known as c.4111G>C), located in coding exon 10 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4111. The glycine at codon 1371 is replaced by arginine, an amino acid with dissimilar properties. One study detected this alteration in 0/1398 patients with unilateral breast cancer and 1/705 patients with contralateral breast cancer (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000688766 SCV000816390 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-05-29 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 Health, Inc RCV000165223 SCV000906470 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 1371 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with breast cancer (PMID: 20104584, 21520273). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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