Submissions for variant NM_007294.4(BRCA1):c.1324T>C (p.Cys442Arg)

dbSNP: rs876660734

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218713	SCV000278391	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-13	criteria provided, single submitter	clinical testing	The p.C442R variant (also known as c.1324T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1324. The cysteine at codon 442 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000218713	SCV000682948	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854712	SCV002260664	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-12-18	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. 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. This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233923). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 442 of the BRCA1 protein (p.Cys442Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218713	SCV003846012	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).