Submissions for variant NM_004656.4(BAP1):c.1217A>T (p.Glu406Val)

gnomAD frequency: 0.00003  dbSNP: rs535695655

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231337	SCV000288735	uncertain significance	BAP1-related tumor predisposition syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 406 of the BAP1 protein (p.Glu406Val). This variant is present in population databases (rs535695655, gnomAD 0.05%). This missense change has been observed in individual(s) with melanoma and breast cancer (PMID: 28062663, 31465090). ClinVar contains an entry for this variant (Variation ID: 240043). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000581007	SCV000682556	likely benign	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000231337	SCV000838040	uncertain significance	BAP1-related tumor predisposition syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000231337	SCV000897129	uncertain significance	BAP1-related tumor predisposition syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581007	SCV001170563	benign	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
GeneDx	RCV001560855	SCV001783346	uncertain significance	not provided	2019-11-21	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 an individual with melanoma (O'Shea 2017); This variant is associated with the following publications: (PMID: 31465090, 28062663)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465594	SCV002760304	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000231337	SCV004214903	uncertain significance	BAP1-related tumor predisposition syndrome	2023-05-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000231337	SCV005404869	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.