rs869025212

Positions:

• chr3-52403427-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.1717del​(p.Leu573TrpfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 5.45

Genes affected

BAP1 (HGNC:950): (BRCA1 associated protein 1) This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52403427-AG-A is Pathogenic according to our data. Variant chr3-52403427-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 221278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1717del	p.Leu573TrpfsTer3	frameshift_variant	13/17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1717del	p.Leu573TrpfsTer3	frameshift_variant	13/17	1	NM_004656.4	ENSP00000417132	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 28, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 10, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 10, 2017	This mutation (deletion of one nucleotide in the BAP1 gene) was identified in a male patient with familial history of melanoma and mesothelioma -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2021	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 17, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	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; Observed frequently in unrelated patients with BAP1-associated malignancy in published literature and described as a European founder variant (PMID: 26683624, 25687217, 26719535, 31206729, 32002398); Not observed at significant frequency 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, 34628055, 30975761, 37556141, 36513904, 32002398, 26683624) -

BAP1 Cancer Syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Thoracic Oncology, University of Hawaii Cancer Center

Oct 01, 2015

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. -

Melanoma, uveal, susceptibility to, 2 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025212; hg19: chr3-52437443;