Submissions for variant NM_007294.4(BRCA1):c.779A>G (p.Lys260Arg)

dbSNP: rs2054049431

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052703	SCV001216927	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-03-13	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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The arginine 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. This sequence change replaces lysine with arginine at codon 260 of the BRCA1 protein (p.Lys260Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333).
Ambry Genetics	RCV002409439	SCV002669077	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	The p.K260R variant (also known as c.779A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 779. The lysine at codon 260 is replaced by arginine, an amino acid with highly similar properties. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002409439	SCV003847946	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).