rs387906848

Variant names:

• chr3-52402608-G-A
• rs387906848
• NM_004656.4:c.2050C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52402608-G-A
• chr3-52402608-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.2050C>T​(p.Gln684*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAP1 NM_004656.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0639 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52402608-G-A is Pathogenic according to our data. Variant chr3-52402608-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30302.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.2050C>T	p.Gln684*	stop_gained	Exon 16 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.2050C>T	p.Gln684*	stop_gained	Exon 16 of 17	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:4

Jan 24, 2025

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.Gln684*) in the BAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the BAP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mesothelioma, skin cancer and uveal melanoma (PMID: 21874000, 24243779). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30302). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BAP1 function (PMID: 18757409). For these reasons, this variant has been classified as Pathogenic. -

Aug 28, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 17, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Feb 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 07, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q684* pathogenic mutation (also known as c.2050C>T), located in coding exon 16 of the BAP1 gene, results from a C to T substitution at nucleotide position 2050. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been previously identified in multiple families affected with BAP1 tumor predisposition syndrome and segregates with disease in these families (Testa JR et al. Nat. Genet. 2011 Oct;43:1022-5; Carbone M et al. J Transl Med. 2012;10:179; Pilarski R et al. Genes Chromosomes Cancer. 2014 Feb;53:177-82; Alakus H et al. J Transl Med. 2015;13:122; Rai K et al. Genes Chromosomes Cancer. 2017 Feb;56:168-174). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Sep 09, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 16 of the BAP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported in individuals affected with mesothelioma, skin carcinoma and uveal melanoma (PMID: 21874000, 24243779 ). This variant has been identified in 1/251330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Apr 04, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 46 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies support a damaging effect: reduced BAP1 protein expression, inactivation of Bap1, and loss of nuclear localization (PMID: 26896281, 35446349); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22935333, 26096145, 24855403, 22683710, 23849051, 38091987, 36451132, 25889843, 24243779, 27882345, 35446349, 26896281, 28665402, 29761599, 21874000, 30975761, 29625052, 26689913) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.92
GERP RS		5.8

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: rs387906848; hg19: chr3-52436624; COSMIC: COSV56230282; COSMIC: COSV56230282;