Submissions for variant NM_004656.4(BAP1):c.1643G>A (p.Arg548His)

gnomAD frequency: 0.00001  dbSNP: rs779877855

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000560956	SCV000672780	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The p.R548H variant (also known as c.1643G>A), located in coding exon 13 of the BAP1 gene, results from a G to A substitution at nucleotide position 1643. The arginine at codon 548 is replaced by histidine, an amino acid with highly similar properties. In a population based study of BAP1 alterations in individuals with melanoma this alteration was detected in one individual diagnosed with cutaneous malignant melanoma at 30 (O'Shea SJ et al. Hum. Mol. Genet., 2017 Jan;). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000560956	SCV000682586	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 548 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 performed for this variant. This variant has been reported in an individual affected with melanoma (PMID: 28062663). This variant has been identified in 3/251088 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	RCV000649781	SCV000771615	uncertain significance	BAP1-related tumor predisposition syndrome	2025-01-23	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 548 of the BAP1 protein (p.Arg548His). This variant is present in population databases (rs779877855, gnomAD 0.006%). This missense change has been observed in individual(s) with malignant melanoma (PMID: 28062663). ClinVar contains an entry for this variant (Variation ID: 485260). 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%. Experimental studies have shown that this missense change does not substantially affect BAP1 function (PMID: 28062663). 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.