Submissions for variant NM_004656.4(BAP1):c.664C>A (p.Pro222Thr)

gnomAD frequency: 0.00001  dbSNP: rs780457225

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774746	SCV000908693	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 222 of the BAP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 25787093). This variant has been identified in 2/249956 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	RCV001227452	SCV001399813	uncertain significance	BAP1-related tumor predisposition syndrome	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 222 of the BAP1 protein (p.Pro222Thr). This variant is present in population databases (rs780457225, gnomAD 0.002%). This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 25787093). ClinVar contains an entry for this variant (Variation ID: 629907). 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 expected to disrupt BAP1 protein function with a positive 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	RCV000774746	SCV002663249	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The p.P222T variant (also known as c.664C>A), located in coding exon 9 of the BAP1 gene, results from a C to A substitution at nucleotide position 664. The proline at codon 222 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported in an Australian melanoma family (Aoude LG et al. Twin Res Hum Genet, 2015 Apr;18:126-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Myriad Genetics, Inc.	RCV001227452	SCV005407574	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.