ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2268G>C (p.Arg756Ser) (rs80356884)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047778 SCV000075791 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 756 of the BRCA1 protein (p.Arg756Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with hereditary breast and ovarian cancer (PMID: 16826315, 24916970). Segregation studies have not been reported for this variant . This variant is also known as 2387G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 54518). 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 serine 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.
Ambry Genetics RCV000129867 SCV000184684 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx RCV000254635 SCV000209935 likely benign not specified 2016-03-17 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.
Counsyl RCV000111812 SCV000489378 uncertain significance Breast-ovarian cancer, familial 1 2016-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254635 SCV000600279 uncertain significance not specified 2017-01-21 criteria provided, single submitter clinical testing
Color RCV000129867 SCV000911273 likely benign Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000254635 SCV000916788 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2268G>C (p.Arg756Ser) 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 allele was found at a frequency of 1.8e-05 in 276934 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.2268G>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Peixoto_2014). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111812 SCV000144361 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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