Submissions for variant NM_004656.4(BAP1):c.755G>A (p.Arg252His)

gnomAD frequency: 0.00001  dbSNP: rs759024400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001026567	SCV001188973	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.R252H variant (also known as c.755G>A), located in coding exon 9 of the BAP1 gene, results from a G to A substitution at nucleotide position 755. The arginine at codon 252 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002551970	SCV003025491	uncertain significance	BAP1-related tumor predisposition syndrome	2024-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 252 of the BAP1 protein (p.Arg252His). This variant is present in population databases (rs759024400, gnomAD 0.002%). 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: 827124). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478660	SCV004221512	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with BAP1-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/251294 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.
Myriad Genetics, Inc.	RCV002551970	SCV005404911	likely benign	BAP1-related tumor predisposition syndrome	2024-07-15	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.