NM_004656.4:c.79dupG

Variant names:

• chr3-52409596-A-AC
• rs397509413
• NM_004656.4:c.79dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.79dupG​(p.Val27GlyfsTer42) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V27V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAP1 NM_004656.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.70
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• BAP1-related tumor predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Kury-Isidor syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 314 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52409596-A-AC is Pathogenic according to our data. Variant chr3-52409596-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 485291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.79dupG	p.Val27GlyfsTer42	frameshift_variant	Exon 3 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.79dupG	p.Val27GlyfsTer42	frameshift_variant	Exon 3 of 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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:1

Oct 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val27Glyfs*42) 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 in individuals with BAP1-related cancer (PMID: 23341325, 28793149). It has also been observed to segregate with disease in related individuals. This variant is also known in the literature as c.75insG (p.Lys25fsX43). ClinVar contains an entry for this variant (Variation ID: 485291). 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

Mar 16, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the BAP1 gene demonstrated a single base pair duplication in exon 3, c.79dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 41 amino acids downstream of the change, p.Val27Glyfs*42. This 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. This duplication has not been described in population databases (gnomAD, ExAC). The p.Val27Glyfs*42 change has previously been described in a patient with peritoneal mesothelioma, and a family history of leukemia, breast, and brain cancer (PMID: 28793149). This duplication has also been reported to segregate with a uveal melanoma phenotype in one family (PMID: 23341325). These collective evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 09, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79dupG pathogenic mutation, located in coding exon 3 of the BAP1 gene, results from a duplication of G at nucleotide position 79, causing a translational frameshift with a predicted alternate stop codon. This mutation was reported to co-segregate with multiple cases of uveal melanoma in a family (H&ouml;iom V et al. Genes Chromosomes Cancer, 2013 Apr;52:378-84). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397509413; hg19: chr3-52443612;