Submissions for variant NM_004656.4(BAP1):c.1833G>C (p.Glu611Asp)

gnomAD frequency: 0.00001  dbSNP: rs771494475

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761021	SCV000890936	uncertain significance	Ganglioglioma	2016-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774726	SCV000908668	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 611 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251440 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.
Invitae	RCV000797507	SCV000937067	uncertain significance	BAP1-related tumor predisposition syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 611 of the BAP1 protein (p.Glu611Asp). This variant is present in population databases (rs771494475, gnomAD 0.003%). 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: 620598). 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%. 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	RCV000774726	SCV001173900	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	clinical testing	The p.E611D variant (also known as c.1833G>C), located in coding exon 14 of the BAP1 gene, results from a G to C substitution at nucleotide position 1833. The glutamic acid at codon 611 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well 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.
GeneDx	RCV001566382	SCV001789888	uncertain significance	not provided	2023-06-06	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; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003411701	SCV004108581	uncertain significance	BAP1-related condition	2023-02-07	criteria provided, single submitter	clinical testing	The BAP1 c.1833G>C variant is predicted to result in the amino acid substitution p.Glu611Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-52437211-C-G) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/620598/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.