Submissions for variant NM_004656.4(BAP1):c.1550C>T (p.Thr517Met)

dbSNP: rs764748646

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649787	SCV000771621	uncertain significance	BAP1-related tumor predisposition syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 517 of the BAP1 protein (p.Thr517Met). This variant is present in population databases (rs764748646, gnomAD 0.003%). This missense change has been observed in individual(s) with a family history of breast cancer (PMID: 30039884). ClinVar contains an entry for this variant (Variation ID: 539914). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000771525	SCV000904061	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 517 of the BAP1 protein. Computational prediction tool 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251120 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	RCV001756088	SCV002005331	uncertain significance	not provided	2023-07-05	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 a family history of breast cancer (Dong et al., 2018); This variant is associated with the following publications: (PMID: 27494029, 30258054, 26452128, 30039884)
Ambry Genetics	RCV000771525	SCV002707455	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-21	criteria provided, single submitter	clinical testing	The p.T517M variant (also known as c.1550C>T), located in coding exon 13 of the BAP1 gene, results from a C to T substitution at nucleotide position 1550. The threonine at codon 517 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly 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.