Submissions for variant NM_004656.4(BAP1):c.1946G>A (p.Cys649Tyr)

gnomAD frequency: 0.00011  dbSNP: rs151308667

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232984	SCV000288747	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 649 of the BAP1 protein (p.Cys649Tyr). This variant is present in population databases (rs151308667, gnomAD 0.02%). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 24166983). ClinVar contains an entry for this variant (Variation ID: 240053). 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: 33240524). 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	RCV000568347	SCV000664603	likely benign	Hereditary cancer-predisposing syndrome	2023-02-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000568347	SCV000902750	likely benign	Hereditary cancer-predisposing syndrome	2016-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001589192	SCV001824688	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: demonstrated nuclear localization and de-ubiquitination activity comparable to wild type (Hong et al., 2020); Observed in individuals with clear cell renal cell carcinoma or unspecified BAP1-related disease (Gossage et al., 2014; Zauderer et al., 2019); This variant is associated with the following publications: (PMID: 28873162, 33240524, 31323388, 24166983)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001589192	SCV002009772	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568347	SCV002537274	likely benign	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267995	SCV002550643	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing