Submissions for variant NM_004656.4(BAP1):c.1751C>A (p.Pro584His)

gnomAD frequency: 0.00001  dbSNP: rs374877744

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468890	SCV000553934	uncertain significance	BAP1-related tumor predisposition syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 584 of the BAP1 protein (p.Pro584His). This variant is present in population databases (rs374877744, gnomAD 0.003%). This missense change has been observed in individual(s) with several cutaneous melanomas and basal cell carcinoma (PMID: 30517737). ClinVar contains an entry for this variant (Variation ID: 412408). 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.
Color Diagnostics, LLC DBA Color Health	RCV000584606	SCV000687959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 584 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 an individual affected with melanoma and basal cell carcinoma (PMID: 30517737). This variant has been identified in 3/251246 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	RCV000584606	SCV001173484	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The p.P584H variant (also known as c.1751C>A), located in coding exon 14 of the BAP1 gene, results from a C to A substitution at nucleotide position 1751. The proline at codon 584 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in a family affected with multiple cutaneous melanomas and basal cell carcinoma (Walpole S et al. J Natl Cancer Inst, 2018 12;110:1328-1341). 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 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.
GeneDx	RCV003223644	SCV003919549	uncertain significance	not provided	2022-10-18	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; Observed in an individual with a personal and/or family history of cutaneous melanoma, basal cell carcinoma, and other cancers (Walpole et al., 2018); This variant is associated with the following publications: (PMID: 30517737)
Baylor Genetics	RCV000468890	SCV004213164	uncertain significance	BAP1-related tumor predisposition syndrome	2023-10-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000468890	SCV005406116	likely benign	BAP1-related tumor predisposition syndrome	2024-07-17	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.