Submissions for variant NM_004656.4(BAP1):c.1555C>T (p.Pro519Ser)

gnomAD frequency: 0.00001  dbSNP: rs759622893

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774125	SCV000907825	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 519 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282492 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064871	SCV001229802	uncertain significance	BAP1-related tumor predisposition syndrome	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 519 of the BAP1 protein (p.Pro519Ser). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 629419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BAP1 protein function with a negative predictive value of 80%. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001064871	SCV001440074	uncertain significance	BAP1-related tumor predisposition syndrome	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001576242	SCV001803388	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001576242	SCV002009778	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000774125	SCV002704364	likely benign	Hereditary cancer-predisposing syndrome	2023-07-25	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001576242	SCV004221268	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	This variant has not been reported in individuals with BAP1-related conditions in the published literature. The frequency of this variant in the general population, 0.00011 (4/35424 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.
Baylor Genetics	RCV001064871	SCV005053263	uncertain significance	BAP1-related tumor predisposition syndrome	2024-02-29	criteria provided, single submitter	clinical testing