Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000473953 | SCV000553926 | uncertain significance | BAP1-related tumor predisposition syndrome | 2022-10-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 590 of the BAP1 protein (p.Gln590Leu). This variant is present in population databases (rs756472919, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 412401). 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 BAP1 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. |
Color Diagnostics, |
RCV000583066 | SCV000687961 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with leucine at codon 590 of the BAP1 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 not been reported in individuals affected with BAP1-related disorders in the literature. This variant has been identified in 2/251362 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. |
Gene |
RCV001775825 | SCV002013517 | uncertain significance | not provided | 2023-04-26 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (Pritchard et al., 2018); Observed in an individual with pancreatic neuroendocrine tumor and another individual with metastatic cancer of unspecified type whose tumor also carried a BAP1 deletion (Cabanillas et al., 2017; Shindo et al., 2017); This variant is associated with the following publications: (PMID: 27123562, 28767289, 28717660, 29641532) |
Ambry Genetics | RCV000583066 | SCV002710647 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-09 | criteria provided, single submitter | clinical testing | The p.Q590L variant (also known as c.1769A>T), located in coding exon 14 of the BAP1 gene, results from an A to T substitution at nucleotide position 1769. The glutamine at codon 590 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in a patient diagnosed with a pancreatic neuroendocrine tumor who underwent genetic testing for hereditary cancer risk via a multi-gene panel (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE. 2018 Apr;13:e0194098). Further, this alteration was observed in the tumor and germline of an individual with metastatic adenocarcinoma of unknown origin; this patient was also identified to have a germline likely pathogenic variant in FANCM (c.4005dupA) (Cabanillas R et al. Mol Genet Genomic Med. 2017 Jul;5:336-359). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Baylor Genetics | RCV000473953 | SCV004213205 | uncertain significance | BAP1-related tumor predisposition syndrome | 2023-10-01 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001775825 | SCV004221310 | uncertain significance | not provided | 2023-07-08 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in an individual with pancreatic ductal adenocarcinoma (PMID: 28767289 (2017)) as well as an unaffected individual (PMID: 29641532 (2018)). Additionally, the variant has been reported in individuals undergoing cancer testing (PMID: 28717660 (2017)). The frequency of this variant in the general population, 0.000008 (2/251362 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |