Submissions for variant NM_004656.4(BAP1):c.1717del (p.Leu573fs)

dbSNP: rs869025212

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Thoracic Oncology, University of Hawaii Cancer Center	RCV000207031	SCV000256058	pathogenic	BAP1 Cancer Syndrome	2015-10-01	criteria provided, single submitter	research	We found 100% penetrance of at least one cancer type in every individual carrying this variant. Our results indicate that this variant has a high prognostic significance.
Invitae	RCV000464745	SCV000553965	pathogenic	BAP1-related tumor predisposition syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu573Trpfs*3) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mesothelioma and uveal melanoma (PMID: 21874000, 25687217, 26683624). This variant is also known as 1832delC. ClinVar contains an entry for this variant (Variation ID: 221278). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000567996	SCV000664583	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The c.1717delC pathogenic mutation, located in coding exon 13 of the BAP1 gene, results from a deletion of one nucleotide at nucleotide position 1717, causing a translational frameshift with a predicted alternate stop codon (p.L573Wfs*3). This mutation has been reported in multiple kindreds with malignant mesothelioma, uveal melanoma, and/or other BAP-1 associated cancers (Cebulla CM et al. Ophthalmic Genet. 2015 Jun;36:126-31; Ohar JA et al. Cancer Res. 2016 Jan;76:206-15; Testa JR et al. Nat. Genet. 2011 Oct;43:1022-5; Carbone M et al. PLoS Genet. 2015 Dec;11:e1005633; Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11; Haugh AM et al. JAMA Dermatol. 2017 Oct;153:999-1006; Hassan R et al. Proc Natl Acad Sci U S A 2019 04;116(18):9008-9013). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000567996	SCV000682589	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 of the BAP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with uveal melanoma, malignant mesothelioma, and melanocytic BAP1-mutated atypical intradermal tumors (MBAITs; PMID: 21874000, 25687217, 26683624, 26719535, 28793149). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000464745	SCV000693457	pathogenic	BAP1-related tumor predisposition syndrome	2017-07-10	criteria provided, single submitter	clinical testing	This mutation (deletion of one nucleotide in the BAP1 gene) was identified in a male patient with familial history of melanoma and mesothelioma
GeneDx	RCV001795342	SCV002032709	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32782288, 21874000, 25687217, 26556299, 27813512, 24705312, 28793149, 31206729, 26748926, 26096145, 24855403, 32547381, 26719535, 30883995, 32002398, 26683624, 34628055, 30975761, 37556141, 36513904)
Genetic Services Laboratory, University of Chicago	RCV001795342	SCV002066588	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BAP1 gene demonstrated a single base pair deletion in exon 13, c.1717del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon three amino acids downstream of the change, p.Leu573Trpfs*3. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BAP1 protein with potentially abnormal function. The c.1717del sequence change has not been described in population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in individual with BAP1-related tumors and cancers (PMID: 32002398, 26719535, 31206729, 28793149, 26683624, 21874000, 25687217). Collectively, these evidences indicated this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively.
Myriad Genetics, Inc.	RCV000464745	SCV003806652	pathogenic	BAP1-related tumor predisposition syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000464745	SCV003836027	pathogenic	BAP1-related tumor predisposition syndrome	2022-11-17	criteria provided, single submitter	clinical testing
OMIM	RCV000464745	SCV000044529	pathogenic	BAP1-related tumor predisposition syndrome	2011-08-28	no assertion criteria provided	literature only
True Health Diagnostics	RCV000567996	SCV000805223	pathogenic	Hereditary cancer-predisposing syndrome	2018-06-05	no assertion criteria provided	clinical testing
OMIM	RCV002273820	SCV002558798	risk factor	Melanoma, uveal, susceptibility to, 2	2022-08-04	no assertion criteria provided	literature only