Submissions for variant NM_007294.4(BRCA1):c.668A>G (p.Lys223Arg)

dbSNP: rs397509306

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853028	SCV002278379	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 223 of the BRCA1 protein (p.Lys223Arg). 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. Studies have shown this missense change is associated with skipping of exon 9, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 23239986). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 55658). This missense change has been observed in individual(s) with breast cancer (PMID: 23239986). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV003584538	SCV004361100	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 223 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). An RNA study has shown that this variant produces a transcript that results in exon 9 skipping, however, in an incomplete manner (PMID: 23239986). Additionally, there is a naturally-occurring BRCA1 mRNA transcript that lacks exons 8 and 9 that retains BRCA1 activity (PMID: 27008870). 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	RCV003584538	SCV005026122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The p.K223R variant (also known as c.668A>G), located in coding exon 8 of the BRCA1 gene, results from an A to G substitution at nucleotide position 668. The lysine at codon 223 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. RNA studies have demonstrated that this alteration results in an incomplete splice defect (Wappenschmidt B et al. PLoS One, 2012 Dec;7:e50800; Ambry internal data); however this variant occurs in an exon that is absent in biologically relevant transcripts (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80) and the clinical impact of this abnormal splicing is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV004589541	SCV005084502	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant been observed in trans with a known pathogenic variant in one or more individuals. Compound heterozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577740	SCV000679637	not provided	Familial cancer of breast		no assertion provided	literature only