Submissions for variant NM_004656.4(BAP1):c.1441C>A (p.His481Asn)

gnomAD frequency: 0.00002  dbSNP: rs764816701

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548144	SCV000651855	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 481 of the BAP1 protein (p.His481Asn). This variant is present in population databases (rs764816701, gnomAD 0.006%). This missense change has been observed in individual(s) with malignant pleural mesothelioma (MPM), which was found in a tumor sample but not confirmed as a germline variant (PMID: 28034829). ClinVar contains an entry for this variant (Variation ID: 472669). 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.
Color Diagnostics, LLC DBA Color Health	RCV000582725	SCV000687932	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with asparagine at codon 481 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 been reported in a family with individuals affected with cutaneous and uveal melanoma (PMID: 30517737). This variant has been identified in 8/282542 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	RCV000582725	SCV001171937	likely benign	Hereditary cancer-predisposing syndrome	2022-04-13	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.
Baylor Genetics	RCV000548144	SCV001481733	uncertain significance	BAP1-related tumor predisposition syndrome	2020-12-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV002473058	SCV002770216	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28034829, 30306255, 30517737)