3-52405163-G-A

Variant names:

• chr3-52405163-G-A
• rs869312757
• NM_004656.4:c.1063C>T

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.1063C>T​(p.Gln355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q355Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.58
• Publications: 5 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52405163-G-A is Pathogenic according to our data. Variant chr3-52405163-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004656.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	NM_004656.4	MANE Select	c.1063C>T	p.Gln355*	stop_gained	Exon 11 of 17	NP_004647.1
	BAP1	NM_001410772.1		c.1009C>T	p.Gln337*	stop_gained	Exon 11 of 17	NP_001397701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	ENST00000460680.6	TSL:1 MANE Select	c.1063C>T	p.Gln355*	stop_gained	Exon 11 of 17	ENSP00000417132.1
	BAP1	ENST00000296288.9	TSL:5	c.1009C>T	p.Gln337*	stop_gained	Exon 11 of 17	ENSP00000296288.5
	BAP1	ENST00000490804.1	TSL:2	n.491C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 05, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q355* pathogenic mutation (also known as c.1063C>T), located in coding exon 11 of the BAP1 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was observed in a patient with a history of melanoma and kidney cancer who underwent multi-gene panel testing (Shirts BH et al. Genet. Med., 2016 Oct;18:974-81). 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.

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BAP1-related tumor predisposition syndrome Pathogenic:1

Jul 22, 2024

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.Gln355*) 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 melanoma and kidney cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224520). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.6
Vest4		0.97
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs869312757; hg19: chr3-52439179; COSMIC: COSV56239587; COSMIC: COSV56239587;