Submissions for variant NM_007294.4(BRCA1):c.2075A>G (p.His692Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002422196	SCV002725715	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	clinical testing	The p.H692R variant (also known as c.2075A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2075. The histidine at codon 692 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with ovarian cancer (Yoshihara K et al. Cancer Sci, 2020 Sep;111:3350-3358). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101040	SCV003338009	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 692 of the BRCA1 protein (p.His692Arg). 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: 1785447). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002422196	SCV003849523	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).