Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192646 | SCV001360900 | likely benign | not specified | 2022-07-11 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.6637T>C (p.Ser2213Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 295768 control chromosomes (gnomAD and Momozawa_2018). In a case-control association study the variant was found at a similar frequency in female breast cancer patients (5/7051) and controls (6/11241) of Japanese ancestry, and the variant was indicated to not be associated with an increased cancer risk (Momozawa 2018). Two co-occurring truncating BRCA variants have also been reported in a Japanese gastric cancer patient (BRCA1 c.188T>A (p.L63X) and BRCA2 c.6922A>T (p.K2308X); Ichikawa_ 2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted an assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Labcorp Genetics |
RCV001304750 | SCV001494044 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-06-21 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2213 of the BRCA2 protein (p.Ser2213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 52142). 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 with a negative predictive value of 95%. 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 | RCV002362672 | SCV002661907 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-26 | criteria provided, single submitter | clinical testing | The p.S2213P variant (also known as c.6637T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 6637. The serine at codon 2213 is replaced by proline, an amino acid with similar properties. This alteration was identified in a Japanese individual diagnosed with gastric cancer (Ichikawa H et al. JCO Precis Oncol, 2018 Jul;2:). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00053 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| University of Washington Department of Laboratory Medicine, |
RCV002362672 | SCV003847324 | 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). |
| Breast Cancer Information Core |
RCV000113617 | SCV000146895 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2003-12-23 | no assertion criteria provided | clinical testing |