Published functional studies support a damaging effect: reduced BAP1 protein expression, inactivation of Bap1, and loss of nuclear localization (Kadariya et al., 2016; Yang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22935333, 26096145, 24855403, 22683710, 23849051, 25889843, 24243779, 27882345, 35446349, 26896281, 28665402, 29761599, 21874000, 30975761, 29625052, 26689913)
ClinVar Genomic variation as it relates to human health
NM_004656.4(BAP1):c.2050C>T (p.Gln684Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004656.4(BAP1):c.2050C>T (p.Gln684Ter)
Variation ID: 30302 Accession: VCV000030302.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.1 3: 52402608 (GRCh38) [ NCBI UCSC ] 3: 52436624 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Jun 17, 2024 Feb 28, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004656.4:c.2050C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004647.1:p.Gln684Ter nonsense NC_000003.12:g.52402608G>A NC_000003.11:g.52436624G>A NG_031859.1:g.12386C>T LRG_529:g.12386C>T LRG_529t1:c.2050C>T - Protein change
- Q684*
- Other names
- -
- Canonical SPDI
- NC_000003.12:52402607:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BAP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2861 | 2878 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 28, 2024 | RCV000023237.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 6, 2023 | RCV000487149.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 7, 2022 | RCV001014205.7 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568804.6
First in ClinVar: Apr 27, 2017 Last updated: Sep 14, 2023 |
Comment:
Published functional studies support a damaging effect: reduced BAP1 protein expression, inactivation of Bap1, and loss of nuclear localization (Kadariya et al., 2016; Yang et … (more)
Published functional studies support a damaging effect: reduced BAP1 protein expression, inactivation of Bap1, and loss of nuclear localization (Kadariya et al., 2016; Yang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22935333, 26096145, 24855403, 22683710, 23849051, 25889843, 24243779, 27882345, 35446349, 26896281, 28665402, 29761599, 21874000, 30975761, 29625052, 26689913) (less)
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Pathogenic
(May 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004045441.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001174887.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
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Pathogenic
(Feb 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005053265.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Sep 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001346840.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000553931.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
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, … (more)
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 protein 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. (less)
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Pathogenic
(Aug 28, 2011)
|
no assertion criteria provided
Method: literature only
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TUMOR PREDISPOSITION SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044528.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 08, 2022 |
Comment on evidence:
In affected members of a 2-generation family from Louisiana with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et … (more)
In affected members of a 2-generation family from Louisiana with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et al. (2011) identified a heterozygous germline C-to-T transition in exon 16 of the BAP1 gene, resulting in a gln684-to-ter (Q684X) substitution. Immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Six mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 2 developed skin cancer (squamous cell and basal cell, respectively), and 1 developed pancreatic cancer. Two family members with prostate cancer did not carry the mutation. (less)
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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.
Comment:
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.
Comment:
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 protein 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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Published functional studies support a damaging effect: reduced BAP1 protein expression, inactivation of Bap1, and loss of nuclear localization (Kadariya et al., 2016; Yang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22935333, 26096145, 24855403, 22683710, 23849051, 25889843, 24243779, 27882345, 35446349, 26896281, 28665402, 29761599, 21874000, 30975761, 29625052, 26689913)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
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.
Comment:
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.
Comment:
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 protein 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline BAP1 alterations in familial uveal melanoma. | Rai K | Genes, chromosomes & cancer | 2017 | PMID: 27718540 |
| BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma. | Alakus H | Journal of translational medicine | 2015 | PMID: 25889843 |
| Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. | Pilarski R | Genes, chromosomes & cancer | 2014 | PMID: 24243779 |
| BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. | Carbone M | Journal of translational medicine | 2012 | PMID: 22935333 |
| Germline BAP1 mutations predispose to malignant mesothelioma. | Testa JR | Nature genetics | 2011 | PMID: 21874000 |
| BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. | Ventii KH | Cancer research | 2008 | PMID: 18757409 |
Text-mined citations for rs387906848 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.