Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000218950 | SCV000279490 | uncertain significance | not provided | 2015-10-09 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.3620A>G at the cDNA level, p.Tyr1207Cys (Y1207C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 3848A>G. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA2 Tyr1207Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr1207Cys occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Tyr1207Cys is pathogenic or benign. |
Labcorp Genetics |
RCV000557673 | SCV000635294 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-07-19 | 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 1207 of the BRCA2 protein (p.Tyr1207Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37848). 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 BRCA2 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. |
Ambry Genetics | RCV000569223 | SCV000665969 | likely benign | Hereditary cancer-predisposing syndrome | 2023-12-28 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. |
Color Diagnostics, |
RCV000569223 | SCV001734002 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-28 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 1207 of the BRCA2 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 been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 1/53460 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008086). This variant has been identified in 1/250896 chromosomes 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. |
University of Washington Department of Laboratory Medicine, |
RCV000569223 | SCV003846740 | 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). |
Sharing Clinical Reports Project |
RCV000031429 | SCV000054034 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2009-02-05 | no assertion criteria provided | clinical testing |