Submissions for variant NM_004656.4(BAP1):c.1045A>G (p.Asn349Asp)

gnomAD frequency: 0.00004  dbSNP: rs765742255

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581746	SCV000687894	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-29	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 349 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 3/277192 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.
Ambry Genetics	RCV000581746	SCV001169899	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.N349D variant (also known as c.1045A>G), located in coding exon 11 of the BAP1 gene, results from an A to G substitution at nucleotide position 1045. The asparagine at codon 349 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060287	SCV001224964	uncertain significance	BAP1-related tumor predisposition syndrome	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 349 of the BAP1 protein (p.Asn349Asp). This variant is present in population databases (rs765742255, gnomAD 0.002%). 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: 490766). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV003236819	SCV003935848	uncertain significance	not provided	2023-06-21	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
Baylor Genetics	RCV001060287	SCV004214883	uncertain significance	BAP1-related tumor predisposition syndrome	2024-03-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001060287	SCV005406081	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.