Submissions for variant NM_004656.4(BAP1):c.1339G>A (p.Val447Ile)

gnomAD frequency: 0.00003  dbSNP: rs762654322

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000534150	SCV000651851	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 447 of the BAP1 protein (p.Val447Ile). This variant is present in population databases (rs762654322, gnomAD 0.02%). This missense change has been observed in individual(s) with uveal melnaoma (PMID: 31058963). ClinVar contains an entry for this variant (Variation ID: 472665). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BAP1 function (PMID: 31058963). 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	RCV000566581	SCV000672781	likely benign	Hereditary cancer-predisposing syndrome	2023-07-06	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	RCV000566581	SCV000682569	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 447 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). A functional study has shown that the variant has no significant impact on the deubiquitinating enzyme activity or the protein cellular localization (PMID: 31058963). This variant has been reported in an individual affected with uveal melanoma (PMID: 31058963). This variant has also been identified in 6/251420 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.
Fulgent Genetics, Fulgent Genetics	RCV000534150	SCV000897128	uncertain significance	BAP1-related tumor predisposition syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000998081	SCV001787796	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with uveal melanoma (Repo 2019); Published functional studies demonstrate deubiquitination ability and protein localization similar to wildtype (Repo 2019); This variant is associated with the following publications: (PMID: 26423602, 31058963)
Baylor Genetics	RCV000534150	SCV004213169	uncertain significance	BAP1-related tumor predisposition syndrome	2023-10-27	criteria provided, single submitter	clinical testing