Submissions for variant NM_004656.4(BAP1):c.1219G>A (p.Asp407Asn)

gnomAD frequency: 0.00003  dbSNP: rs765347562

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000549973	SCV000651849	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 407 of the BAP1 protein (p.Asp407Asn). This variant is present in population databases (rs765347562, gnomAD 0.01%). 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: 472663). 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	RCV000568816	SCV000672773	likely benign	Hereditary cancer-predisposing syndrome	2021-11-11	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	RCV000568816	SCV000903309	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 407 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 BAP1-related disorders in the literature. This variant has been identified in 19/280318 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.
Genetic Services Laboratory, University of Chicago	RCV001821594	SCV002066243	uncertain significance	not specified	2021-04-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BAP1 gene demonstrated a sequence change, c.1219G>A, in exon 12 that results in an amino acid change, p.Asp407Asn. This sequence change has been described in gnomAD with a population frequency of 0.014% in the Non-Finnish European sub-population (dbSNP rs765347562). The p.Asp407Asn change affects a poorly conserved amino acid residue located in a domain of the BAP1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp407Asn substitution. This sequence change does not appear to have been previously described in patients with BAP1-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Asp407Asn change remains unknown at this time.
GeneDx	RCV002225659	SCV002503996	uncertain significance	not provided	2023-03-10	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001821594	SCV002760302	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409813	SCV004108914	uncertain significance	BAP1-related condition	2023-05-17	criteria provided, single submitter	clinical testing	The BAP1 c.1219G>A variant is predicted to result in the amino acid substitution p.Asp407Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-52438500-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/472663/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.