Submissions for variant NM_004656.4(BAP1):c.821A>C (p.His274Pro)

dbSNP: rs565400314

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000296120	SCV000445479	likely benign	BAP1-related tumor predisposition syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000580769	SCV000682650	likely benign	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing
Invitae	RCV000296120	SCV001388473	uncertain significance	BAP1-related tumor predisposition syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 274 of the BAP1 protein (p.His274Pro). This variant is present in population databases (rs565400314, gnomAD 0.04%). 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: 346123). 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.
Ambry Genetics	RCV000580769	SCV002678292	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	clinical testing	The p.H274P variant (also known as c.821A>C), located in coding exon 10 of the BAP1 gene, results from an A to C substitution at nucleotide position 821. The histidine at codon 274 is replaced by proline, an amino acid with similar properties. 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.