Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219923 | SCV000276840 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-24 | criteria provided, single submitter | clinical testing | The p.H1195Y variant (also known as c.3583C>T and 3702C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3583. The histidine at codon 1195 is replaced by tyrosine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort. 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 p.H1195Y remains unclear. |
| Invitae | RCV001070488 | SCV001235735 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-03-01 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1195 of the BRCA1 protein (p.His1195Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 232653). 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000219923 | SCV003848403 | 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). |