Submissions for variant NM_007294.4(BRCA1):c.1114T>C (p.Trp372Arg)

dbSNP: rs1306111238

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574370	SCV000673069	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-18	criteria provided, single submitter	clinical testing	The p.W372R variant (also known as c.1114T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1114. The tryptophan at codon 372 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is 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.
Invitae	RCV000637338	SCV000758790	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 372 of the BRCA1 protein (p.Trp372Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 485404). 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%. 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.
GeneDx	RCV002509450	SCV002819032	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1233T>C
University of Washington Department of Laboratory Medicine, University of Washington	RCV000574370	SCV003846161	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).