Submissions for variant NM_007294.4(BRCA1):c.1856A>G (p.His619Arg)

dbSNP: rs771890863

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000470518	SCV000549419	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-04	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 619 of the BRCA1 protein (p.His619Arg). 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: 409369). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001186645	SCV001353152	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 619 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. 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.
Sema4, Sema4	RCV001186645	SCV002538056	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-29	criteria provided, single submitter	curation
Ambry Genetics	RCV001186645	SCV002722112	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The p.H619R variant (also known as c.1856A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1856. The histidine at codon 619 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001186645	SCV003849689	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).