Submissions for variant NM_004656.4(BAP1):c.1669A>G (p.Ile557Val)

gnomAD frequency: 0.00001  dbSNP: rs776549962

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000688048	SCV000815645	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 557 of the BAP1 protein (p.Ile557Val). This variant is present in population databases (rs776549962, 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: 567857). 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	RCV001179583	SCV001344279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 557 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 2/251006 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.
GeneDx	RCV001775956	SCV002014010	uncertain significance	not provided	2023-04-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with cutaneous melanoma (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080)
Ambry Genetics	RCV001179583	SCV002706110	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	The p.I557V variant (also known as c.1669A>G), located in coding exon 13 of the BAP1 gene, results from an A to G substitution at nucleotide position 1669. The isoleucine at codon 557 is replaced by valine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465753	SCV002760300	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000688048	SCV004214900	uncertain significance	BAP1-related tumor predisposition syndrome	2023-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001775956	SCV004221283	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with skin cutaneous melanoma (PMID: 29684080 (2018)). The frequency of this variant in the general population, 0.000008 (2/251006 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.
PreventionGenetics, part of Exact Sciences	RCV003892531	SCV004713934	uncertain significance	BAP1-related condition	2023-10-19	criteria provided, single submitter	clinical testing	The BAP1 c.1669A>G variant is predicted to result in the amino acid substitution p.Ile557Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-52437492-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.