Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165983 | SCV000216741 | likely benign | Hereditary cancer-predisposing syndrome | 2019-01-18 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Invitae | RCV001342447 | SCV001536380 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1522 of the BRCA1 protein (p.Tyr1522Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 19190334). ClinVar contains an entry for this variant (Variation ID: 55228). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30765603). 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. |
| Genetic Services Laboratory, |
RCV001818228 | SCV002070133 | uncertain significance | not specified | 2020-02-06 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4565A>G, in exon 14 that results in an amino acid change, p.Tyr1522Cys. This sequence change has not been described in population databases (gnomAD, ExAC). Functional studies demonstrated no impact on protein function in the presence of this sequence change (PMID: 28781887). The p.Tyr1522Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Tyr1522Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Tyr1522Cys change remains unknown at this time. |
| Breast Cancer Information Core |
RCV000112358 | SCV000145119 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing |