Submissions for variant NM_004656.4(BAP1):c.1781G>C (p.Gly594Ala)

gnomAD frequency: 0.00006  dbSNP: rs144172190

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554337	SCV000651864	uncertain significance	BAP1-related tumor predisposition syndrome	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 594 of the BAP1 protein (p.Gly594Ala). This variant is present in population databases (rs144172190, gnomAD 0.01%). 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: 472678). 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.
Ambry Genetics	RCV000566252	SCV000672732	likely benign	Hereditary cancer-predisposing syndrome	2020-11-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000566252	SCV000682597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 594 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 18/251384 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.
GeneDx	RCV001785658	SCV002027868	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV000554337	SCV005404790	likely benign	BAP1-related tumor predisposition syndrome	2024-07-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001785658	SCV005625009	uncertain significance	not provided	2024-02-14	criteria provided, single submitter	clinical testing	The BAP1 c.1781G>C (p.Gly594Ala) variant has not been reported in individuals with BAP1-related conditions in the published literature. The frequency of this variant in the general population, 0.00012 (2/16252 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.