Submissions for variant NM_007294.4(BRCA1):c.820T>C (p.Cys274Arg)

dbSNP: rs755285181

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001043878	SCV001207645	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-04-08	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 274 of the BRCA1 protein (p.Cys274Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine.
Color Diagnostics, LLC DBA Color Health	RCV001525555	SCV001735711	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 274 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Ambry Genetics	RCV001525555	SCV002678276	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-11	criteria provided, single submitter	clinical testing	The p.C274R variant (also known as c.820T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 820. The cysteine at codon 274 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001525555	SCV003847915	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).