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.
ClinVar Genomic variation as it relates to human health
NM_004656.4(BAP1):c.1777C>T (p.Gln593Ter)
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.
(6)
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
6
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.1777C>T (p.Gln593Ter)
Variation ID: 422219 Accession: VCV000422219.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.1 3: 52403251 (GRCh38) [ NCBI UCSC ] 3: 52437267 (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 May 1, 2024 Oct 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004656.4:c.1777C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004647.1:p.Gln593Ter nonsense NC_000003.12:g.52403251G>A NC_000003.11:g.52437267G>A NG_031859.1:g.11743C>T LRG_529:g.11743C>T LRG_529t1:c.1777C>T - Protein change
- Q593*
- Other names
- -
- Canonical SPDI
- NC_000003.12:52403250:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
- 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 |
2930 | 2947 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 19, 2023 | RCV000483505.2 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 17, 2023 | RCV000763519.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 11, 2021 | RCV001013141.3 |
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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|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894325.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Sep 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000571628.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jul 09, 2021)
|
criteria provided, single submitter
Method: research
|
BAP1-related tumor predisposition syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal,
unknown
|
Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV001748998.1
First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021 |
Comment:
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 … (more)
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. (less)
Observation 1:
Age: 20-29 years
Sex: female
Observation 2:
Age: 50-59 years
Sex: female
|
|
|
Pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001586477.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Mar 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001173685.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
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 … (more)
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 mutation has been described multiple individuals 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. (less)
|
|
|
Pathogenic
(Sep 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221320.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
|
Comment:
Comment:
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.
Comment:
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.
Comment:
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 mutation has been described multiple individuals 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.
Comment:
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.
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:
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.
Comment:
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.
Comment:
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.
Comment:
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 mutation has been described multiple individuals 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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Meningiomas in Patients With Malignant Pleural Mesothelioma Harboring Germline BAP1 Mutations. | Hu ZI | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | 2022 | PMID: 34628055 |
| Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas. | Guo R | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | 2020 | PMID: 31887429 |
| Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors. | Garfield EM | Journal of the American Academy of Dermatology | 2018 | PMID: 29753057 |
| A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer. | McDonnell KJ | Cancer genetics | 2016 | PMID: 26774355 |
| Germline BAP1 mutations predispose to renal cell carcinomas. | Popova T | American journal of human genetics | 2013 | PMID: 23684012 |
| Germline BAP1 mutations predispose to malignant mesothelioma. | Testa JR | Nature genetics | 2011 | PMID: 21874000 |
Text-mined citations for rs1064795638 ...
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.