Submissions for variant NM_004656.4(BAP1):c.944A>C (p.Glu315Ala)

gnomAD frequency: 0.00004  dbSNP: rs149974450

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472838	SCV000553932	uncertain significance	BAP1-related tumor predisposition syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 315 of the BAP1 protein (p.Glu315Ala). This variant is present in population databases (rs149974450, gnomAD 0.02%). This missense change has been observed in individual(s) with renal cell carcinoma and malignant pleural mesothelioma (PMID: 28687356, 31034483). ClinVar contains an entry for this variant (Variation ID: 412406). 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	RCV000565342	SCV000672775	likely benign	Hereditary cancer-predisposing syndrome	2020-08-17	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.
Color Diagnostics, LLC DBA Color Health	RCV000565342	SCV000682659	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 315 of the BAP1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual each affected with malignant pleural mesothelioma (PMID: 28687356) and an individual affected with renal cell carcinoma (PMID: 31034483). This variant has also been identified in 26/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and reported in two individuals over age 70 without cancer (FLOSSIES). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000472838	SCV001737437	uncertain significance	BAP1-related tumor predisposition syndrome	2021-06-10	criteria provided, single submitter	clinical testing	The BAP1 c.944A>C (p.Glu315Ala)missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/3-52439298-T-G?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with renal cell carcinoma, malignant mesothelioma, and pediatric osteosarcoma (PMID: 31034483, 28687356, 26580448). It is present 2X in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/variant/3-52439298-T-G). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
GeneDx	RCV001562013	SCV001784714	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of renal cancer, osteosarcoma, or mesothelioma (PMID: 26580448, 28687356, 31034483); This variant is associated with the following publications: (PMID: 21642991, 26659599, 28687356, 26580448, 31034483, 34711244)
Myriad Genetics, Inc.	RCV000472838	SCV005404748	likely benign	BAP1-related tumor predisposition syndrome	2024-07-15	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.