Submissions for variant NM_007294.4(BRCA1):c.3585T>A (p.His1195Gln)

dbSNP: rs2053561125

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001216829	SCV001388642	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1195 of the BRCA1 protein (p.His1195Gln). ClinVar contains an entry for this variant (Variation ID: 946048). 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.
Color Diagnostics, LLC DBA Color Health	RCV001524003	SCV001733756	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-24	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 1195 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.
Ambry Genetics	RCV001524003	SCV002613373	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-17	criteria provided, single submitter	clinical testing	The p.H1195Q variant (also known as c.3585T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 3585. The histidine at codon 1195 is replaced by glutamine, 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	RCV001524003	SCV003848370	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).