Submissions for variant NM_004656.4(BAP1):c.1345G>A (p.Ala449Thr)

gnomAD frequency: 0.00002  dbSNP: rs764734266

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562229	SCV000672786	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.A449T variant (also known as c.1345G>A), located in coding exon 13 of the BAP1 gene, results from a G to A substitution at nucleotide position 1345. The alanine at codon 449 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in 1 of 507 patients with uveal melanoma from a retrospective cohort study (Gupta MP et al, JAMA Ophthalmol 2015 Aug; 133(8):881-7). 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.
Invitae	RCV000649805	SCV000771639	uncertain significance	BAP1-related tumor predisposition syndrome	2023-04-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 485264). This missense change has been observed in individual(s) with uveal melanoma (PMID: 25974357). This variant is present in population databases (rs764734266, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 449 of the BAP1 protein (p.Ala449Thr).
Color Diagnostics, LLC DBA Color Health	RCV000562229	SCV000908680	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 449 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. The variant has been observed in an individual affected with uveal melanoma (PMID: 25974357). This variant has been identified in 1/251396 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	RCV001770520	SCV002004344	uncertain significance	not provided	2019-12-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with uveal melanoma (Gupta 2015); This variant is associated with the following publications: (PMID: 29761599, 25974357, 29625052)