Submissions for variant NM_004656.4(BAP1):c.1212C>G (p.Asp404Glu)

gnomAD frequency: 0.00011  dbSNP: rs140998455

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461066	SCV000553953	uncertain significance	BAP1-related tumor predisposition syndrome	2022-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 404 of the BAP1 protein (p.Asp404Glu). This variant is present in population databases (rs140998455, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412427). 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. 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	RCV000568684	SCV000672776	benign	Hereditary cancer-predisposing syndrome	2017-02-14	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.
Color Diagnostics, LLC DBA Color Health	RCV000568684	SCV000911425	likely benign	Hereditary cancer-predisposing syndrome	2017-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001584169	SCV001820883	uncertain significance	not provided	2020-02-12	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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000461066	SCV002584663	uncertain significance	BAP1-related tumor predisposition syndrome	2022-09-26	criteria provided, single submitter	clinical testing	The BAP1 c.1212C>G (p.Asp404Glu) missense change has a maximum subpopulation frequency of 0.036% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with BAP1-related tumor predisposition syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003409639	SCV004113755	likely benign	BAP1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).