chr3-52409596-AC-A

Position:

• chr3-52409596-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.79delG​(p.Val27fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAP1 NM_004656.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.70

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]

BAP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52409596-AC-A is Pathogenic according to our data. Variant chr3-52409596-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 945509.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.79delG	p.Val27fs	frameshift_variant	3/17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.79delG	p.Val27fs	frameshift_variant	3/17	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2019

This sequence change creates a premature translational stop signal (p.Val27Cysfs*45) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with mesothelioma in a family (PMID: 23032617) and has been observed in individuals with mesothelioma, melanocytic tumor, and uveal melanoma (PMID: 23032617, 30477459). Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Jun 23, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2020

The c.79delG pathogenic mutation, located in coding exon 3 of the BAP1 gene, results from a deletion of one nucleotide at nucleotide position 79, causing a translational frameshift with a predicted alternate stop codon (p.V27Cfs*45). This mutation has been reported in a 34-year-old proband diagnosed with pleural mesothelioma, peritoneal mesothelioma, and melanocytic papular skin tumors which demonstrated loss of BAP1 staining on immunohistochemistry. Her sister with mesothelioma diagnosed at 44 years and her mother with a peritoneal mesothelioma also tested positive for BAP1 c.79delG, while her unaffected father was negative for the mutation (Wiesner T et al. J. Clin. Oncol. 2012 Nov;30(32):e337-40). This mutation has also been reported in the germline of a proband diagnosed with uveal melanoma (Ewens K et al. BMC Cancer 2018 Nov;18(1):1172). 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. -

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: rs397509413; hg19: chr3-52443612;