Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000507648 | SCV000600622 | uncertain significance | not specified | 2016-08-05 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001023445 | SCV001185322 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-22 | criteria provided, single submitter | clinical testing | The p.P168A variant (also known as c.502C>G), located in coding exon 5 of the BRCA2 gene, results from a C to G substitution at nucleotide position 502. The proline at codon 168 is replaced by alanine, an amino acid with highly similar properties. This alteration was identified in 1/278 individuals from a cohort BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8), and was also detected in 1/100 Jordanian breast cancer patients (Abdel-Razeq H et al. BMC Cancer, 2018 Feb;18:152). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001306508 | SCV001495883 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 168 of the BRCA2 protein (p.Pro168Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 29409476, 34290354). ClinVar contains an entry for this variant (Variation ID: 126130). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000507648 | SCV002511979 | uncertain significance | not specified | 2023-11-07 | criteria provided, single submitter | clinical testing | Variant summary: BRCA2 c.502C>G (p.Pro168Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-06 in 273952 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.502C>G has been reported in the literature in individuals affected with breast cancer, without strong evidence for causality (e.g. Abdel-Razeq_2018, Abdel-Razeq_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29409476, 35402282, 34290354, 32467295). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV003474702 | SCV004211866 | uncertain significance | Familial cancer of breast | 2023-10-16 | criteria provided, single submitter | clinical testing | |
| Breast Cancer Information Core |
RCV000113705 | SCV000147018 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2004-02-20 | no assertion criteria provided | clinical testing |