Submissions for variant NM_007294.4(BRCA1):c.804C>G (p.Asn268Lys)

dbSNP: rs771076131

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000510083	SCV000607788	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.N268K variant (also known as c.804C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 804. The asparagine at codon 268 is replaced by lysine, an amino acid with similar properties. This alteration was detected in a cohort of 212 Italian ovarian cancer patients (Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000510083	SCV000688664	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985447	SCV001133647	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000099 (3/30418 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 26306726 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857299	SCV002143163	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 268 of the BRCA1 protein (p.Asn268Lys). This variant is present in population databases (rs771076131, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 26306726, 29020660). ClinVar contains an entry for this variant (Variation ID: 441285). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 32546644). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510083	SCV003847929	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003227773	SCV003924372	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-15	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the BRCA1 gene (c.804C>G). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 268 of the BRCA1 protein (p.Asn268Lys). This variant is present in population databases (rs771076131, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 26306726, 29020660). ClinVar contains an entry for this variant (Variation ID: 441285). This amino acid position is not well conserved ( PhyloP=2.65) . In addition, this alteration is predicted to be tolerated by in silico analysis. 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.
MGZ Medical Genetics Center	RCV003607297	SCV004543885	benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS3