ClinVar Miner

Submissions for variant NM_007294.4(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 2020-09-15 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, 30702160). 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 The p.R756S variant (also known as c.2268G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2268. The arginine at codon 756 is replaced by serine, an amino acid with dissimilar properties. This alteration was seen in a cohort of Portuguese breast and ovarian cancer families who were selected for BRCA1/2 screening based on clinical criteria or their BRCAPRO score and was classified as a variant of unknown significance (Peixoto A et al. Clin. Genet. 2015 Jul;88:41-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001281712 SCV000209935 likely benign not provided 2019-06-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16826315, 24916970)
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 RCV001281712 SCV000600279 uncertain significance not provided 2019-08-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129867 SCV000911273 likely benign Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254635 SCV000916788 uncertain significance not specified 2019-08-30 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 8e-06 in 251210 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2268G>C has been reported in the literature in individuals affected with Hereditary/familial 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, uncertain significance, n=4). 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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