Submissions for variant NM_004656.4(BAP1):c.1820C>T (p.Thr607Met)

gnomAD frequency: 0.00001  dbSNP: rs770654975

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471550	SCV000553966	uncertain significance	BAP1-related tumor predisposition syndrome	2023-08-11	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: 412439). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. This variant is present in population databases (rs770654975, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 607 of the BAP1 protein (p.Thr607Met).
Color Diagnostics, LLC DBA Color Health	RCV000774727	SCV000908669	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 607 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 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 6/251404 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.
Mendelics	RCV000471550	SCV001136531	uncertain significance	BAP1-related tumor predisposition syndrome	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001539588	SCV001757376	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27149842)
Sema4, Sema4	RCV000774727	SCV002537268	likely benign	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
Ambry Genetics	RCV000774727	SCV002711075	likely benign	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.