Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Mendelics | RCV000112654 | SCV001140466 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Breast Cancer Information Core |
RCV000112654 | SCV000145512 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 1997-11-14 | no assertion criteria provided | clinical testing | |
Brotman Baty Institute, |
RCV000112654 | SCV001238384 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro | ||
Department of Pathology and Laboratory Medicine, |
RCV001355658 | SCV001550602 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BRCA1 p.Val1810Gly variant was identified in 1 of 1978 proband chromosomes (frequency: 0.0005) from individuals or families with breast or ovarian cancer (Meindl 2002). The variant was identified in dbSNP (rs80357451) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by BIC), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 1x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 transactivation activity but did not alter protein stability and binding; these discordant results led the authors to classify this variant as having an uncertain effect on protein function (Lee 2010). The p.Val1810 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. |