Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216219 | SCV000274838 | likely benign | Hereditary cancer-predisposing syndrome | 2020-03-04 | 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. |
| Labcorp Genetics |
RCV000637359 | SCV000758814 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-09-22 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 231093). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2966 of the BRCA2 protein (p.Val2966Ala). |
| Color Diagnostics, |
RCV000216219 | SCV001347348 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-05 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with alanine at codon 2966 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant as functionally proficient in homology-directed DNA repair and rescue of cisplatin sensitivity assays (PMID: 29884841, 29988080). This variant has been reported in individual(s) who met Dutch clinical genetic testing guideline (PMID: 29988080). This variant has been identified in 1/249904 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. |
| Fulgent Genetics, |
RCV005008162 | SCV005633992 | uncertain significance | Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer | 2024-05-02 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001357680 | SCV001553217 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The BRCA2 p.Val2966Ala variant was identified in the literature however the frequency of this variant in an affected population was not provided (Mesman 2019). The variant was also identified in dbSNP (ID: rs876658955) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics and Invitae).The variant was not identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in control databases in 1 of 244734 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 110710 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In a mouse embryonic stem cell (mESC)-based functional assay evaluating complementation by BRCA2 variants of the cell lethal phenotype imposed by Cre-mediated loss of Brca2 as visualized by methylene blue (MB) staining of arising hypoxanthine–aminopterin–thymidine (HAT) resistant clones, as well as homology directed repair (HDR) and sensitivity to the DNA crosslinking agent cisplatin, this variant demonstrated positive MB staining, 62% HDR activity and 65% cisplatin sensitivity, which was comparable to the nonpathogenic variants tested, and suggests a more neutral role for this variant (Mesman 2019). The p.Val2966 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |