Submissions for variant NM_004656.4(BAP1):c.1408G>A (p.Gly470Arg)

gnomAD frequency: 0.00012  dbSNP: rs576538858

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471822	SCV000553923	uncertain significance	BAP1-related tumor predisposition syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 470 of the BAP1 protein (p.Gly470Arg). This variant is present in population databases (rs576538858, gnomAD 0.03%). This missense change has been observed in individual(s) with thyroid carcinoma (PMID: 29684080). ClinVar contains an entry for this variant (Variation ID: 133663). 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.
Ambry Genetics	RCV000574998	SCV000672757	likely benign	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Mendelics	RCV003492520	SCV000838038	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574998	SCV000902856	likely benign	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001527719	SCV001738846	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 thyroid cancer and healthy individuals under age 50 undergoing whole genome sequencing (Bodian 2014, Yehia 2018); This variant is associated with the following publications: (PMID: 30480620, 24728327, 29684080)
Sema4, Sema4	RCV000574998	SCV002537259	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001527719	SCV004220464	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with thyroid cancer (PMID: 29684080 (2018)), and in healthy individuals under the age of 50 (PMID: 24728327 (2014)). It has also been reported as a somatic variant in an individual with uveal melanoma (PMID: 30480620 (2019)). The frequency of this variant in the general population, 0.00023 (8/34582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000471822	SCV005404769	likely benign	BAP1-related tumor predisposition syndrome	2024-07-16	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.
ITMI	RCV000120191	SCV000084337	not provided	not specified	2013-09-19	no assertion provided	reference population
GenomeConnect - Invitae Patient Insights Network	RCV000471822	SCV004228670	not provided	BAP1-related tumor predisposition syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-22-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004751272	SCV005352241	uncertain significance	BAP1-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The BAP1 c.1408G>A variant is predicted to result in the amino acid substitution p.Gly470Arg. This variant has been reported in one individual with thyroid cancer (Yehia L et al. 2018. PubMed ID: 29684080) and as a somatic variant in one individual with uveal melanoma (Sarubi HC et al. 2019. PubMed ID: 30480620). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from a variant of uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/133663/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.