Submissions for variant NM_004656.4(BAP1):c.1721C>T (p.Ala574Val)

gnomAD frequency: 0.00001  dbSNP: rs761596789

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464695	SCV000553948	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 574 of the BAP1 protein (p.Ala574Val). This variant is present in population databases (rs761596789, gnomAD 0.003%). This missense change has been observed in individual(s) with uveal melanoma (PMID: 25974357). ClinVar contains an entry for this variant (Variation ID: 412422). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000581388	SCV000687951	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 574 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 assays have not been performed for this variant. This variant has been reported in an individual affected with uveal melanoma (PMID: 25974357) and in a control individual (PMID: 28062663). This variant has also been identified in 4/250416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV000581388	SCV001173357	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	The p.A574V variant (also known as c.1721C>T), located in coding exon 13 of the BAP1 gene, results from a C to T substitution at nucleotide position 1721. The alanine at codon 574 is replaced by valine, an amino acid with similar properties. This variant was reported in 1/507 patients with uveal melanoma (Gupta MP et al. JAMA Ophthalmol. 2015 Aug;133:881-7). However, in a case-control study this variant was not observed in 1977 melanoma cases but was seen in 1/754 controls (O'Shea SJ et al. Hum. Mol. Genet. 2017 02;26:717-728). 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.
GeneDx	RCV001356458	SCV002526276	uncertain significance	not provided	2022-06-08	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; Observed in individuals with melanoma and also in unaffected controls (Gupta 2015, O'Shea 2017); This variant is associated with the following publications: (PMID: 25974357, 28062663, 34426522)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001356458	SCV004221295	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with uveal melanoma (PMID: 25974357 (2015)) as well as unaffected individuals (PMID: 34426522 (2021), 28062663 (2017)). The frequency of this variant in the general population, 0.000016 (4/250416 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356458	SCV001551635	uncertain significance	not provided		no assertion criteria provided	clinical testing