chr3-52403251-G-A

Variant names:

• chr3-52403251-G-A
• rs1064795638
• NM_004656.4:c.1777C>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.1777C>T​(p.Gln593*) variant causes a stop gained change. 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 (★★). 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:6
• Conservation: PhyloP100: 5.27
• Publications: 10 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 3-52403251-G-A is Pathogenic according to our data. Variant chr3-52403251-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 422219.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.1777C>T	p.Gln593*	stop_gained	Exon 14 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1777C>T	p.Gln593*	stop_gained	Exon 14 of 17	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:3

Oct 17, 2023

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.Gln593*) 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 BAP1 tumor predisposition syndrome (PMID: 26774355). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 422219). For these reasons, this variant has been classified as Pathogenic. -

Jul 09, 2021

Institute for Genomic Medicine, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.1777C>T variant is predicted to cause a nonsense change at residue 593 of the BAP1 protein. It is absent from large public databases including gnomAD, and has been recently reported as pathogenic by multiple clinical laboratories. This variant was observed in a mother and daughter who developed meningiomas with rhabdoid features. We interpret the variant as pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Sep 09, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BAP1 c.1777C>T at the cDNA level and p.Gln593Ter (Q593X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. McDonnell et al (2016) identified BAP1 Gln593Ter in an individual with a personal history of melanoma, thyroid neoplasia, basal cell carcinoma, and lymphoma and a family history of Spitz nevi, melanoma, and other cancers. Tumors from the proband and her sons demonstrated loss of the BAP1 protein by immunohistochemistry, and this variant segregated with disease in the family. We consider this variant to be pathogenic. -

Sep 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BAP1 c.1777C>T (p.Gln593*) variant causes the premature termination of BAP1 protein synthesis. This variant has been reported in the published literature in individuals with meningioma (PMID: 34628055 (2022)), melanoma (PMID: 31887429 (2020)). The variant also has been observed in an individual with multiple cancers such as papillary thyroid cancer, b-cell lymphoma, and basal cell carcinoma (PMID: 26774355 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q593* pathogenic mutation (also known as c.1777C>T), located in coding exon 14 of the BAP1 gene, results from a C to T substitution at nucleotide position 1777. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This variant has been described multiple individuals diagnosed with BAP1-related cancers (McDonnell KJ et al. Cancer Genet, 2016 Mar;209:75-81; Garfield EM et al. J Am Acad Dermatol, 2018 Sep;79:525-534; Guo R et al. J Thorac Oncol, 2020 04;15:655-660). 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.3
Vest4		0.84
GERP RS		5.8
PromoterAI		-0.0048	Neutral
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)		0.020		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: rs1064795638; hg19: chr3-52437267; COSMIC: COSV99964648;