ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2268G>T (p.Arg756Ser) (rs80356884)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240783 SCV000265874 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Color Health, Inc RCV000777927 SCV000913981 likely benign Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000777927 SCV001175768 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing The p.R756S variant (also known as c.2268G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2268. The arginine at codon 756 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in 1/507 individuals from a Chinese unselected breast cancer cohort (Zhong X et al. PLoS ONE 2016 Jun;11(6):e0156789). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
Invitae RCV001043803 SCV001207568 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-08 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 observed in individual(s) affected with breast and/or ovarian cancer (PMID: 27257965, 30702160). ClinVar contains an entry for this variant (Variation ID: 224428). 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.

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