ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4131_4132insTGAGGA (p.Thr1378Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.4131_4132insTGAGGA (p.Thr1378Ter)
Variation ID: 126037 Accession: VCV000126037.27
- Type and length
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Insertion, 6 bp
- Location
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Cytogenetic: 13q13.1 13: 32338486-32338487 (GRCh38) [ NCBI UCSC ] 13: 32912623-32912624 (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 4, 2014 May 1, 2024 Oct 18, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.4131_4132insTGAGGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr1378Ter nonsense NC_000013.11:g.32338486_32338487insTGAGGA NC_000013.10:g.32912623_32912624insTGAGGA NG_012772.3:g.28007_28008insTGAGGA LRG_293:g.28007_28008insTGAGGA LRG_293t1:c.4131_4132insTGAGGA LRG_293p1:p.Thr1378Ter U43746.1:n.4359_4360insTGAGGA - Protein change
- T1378*
- Other names
- 1377insXG
- 4359ins6
- Canonical SPDI
- NC_000013.11:32338486::TGAGGA
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18726 | 18884 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
reviewed by expert panel
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Oct 18, 2016 | RCV000113276.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000215361.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000465953.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 29, 2021 | RCV000485082.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2022 | RCV002247496.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2022 | RCV002477264.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2022 | RCV003492436.1 |
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 18, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000324219.2
First in ClinVar: Apr 04, 2014 Last updated: Feb 07, 2023 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Sep 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694745.2
First in ClinVar: Apr 17, 2017 Last updated: Oct 10, 2020 |
Comment:
Variant summary: BRCA2 c.4131_4132insTGAGGA (p.Thr1378X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.4131_4132insTGAGGA (p.Thr1378X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246356 control chromosomes (gnomAD). c.4131_4132insTGAGGA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Delgado_2002, Palma_2008, Ding_2011, Nicolussi_2019, Vietri_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000688851.3
First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021 |
Comment:
This variant inserts 6 nucleotides in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant inserts 6 nucleotides in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 11890985, 18703817, 20927582, 23096105, 25940717, 32438681). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000564776.3
First in ClinVar: Apr 27, 2017 Last updated: Dec 19, 2017 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4359_4360insTGAGGA or 4359ins6; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27535533, 31447099, 31065452, 30128899, 31209999, 29907814, 25896959, 27376475, 25940717, 11890985, 20927582) (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518603.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326976.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(May 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Malignant tumor of prostate Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002796232.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210518.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296512.3
First in ClinVar: Apr 04, 2014 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with personal and/or family history of … (more)
This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with personal and/or family history of breast and/or ovarian in the published literature (PMIDs: 11890985 (2002), 23096105 (2012), 25896959 (2015), 27376475 (2016), 31065452 (2019), 32438681 (2020), and 33471991 (2021)). The variant has also been identified in one individual with pancreatic ductal adenocarcinoma (PMID: 25940717 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Sep 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004240310.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000549711.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Thr1378*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Thr1378*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pancreatic ductal adenocarcinoma and a personal and/or family history of breast cancer (PMID: 11890985, 20927582, 23096105, 25896959, 25940717, 27376475). This variant is also known as Ins 4359 (TGAGGA), 4359ins6, or 1377insXG (InsTGAGGA). ClinVar contains an entry for this variant (Variation ID: 126037). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000276996.5
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.4131_4132insTGAGGA pathogenic mutation (also known as p.T1378*), located in coding exon 10 of the BRCA2 gene, results from an in-frame TGAGGA insertion between nucleotide … (more)
The c.4131_4132insTGAGGA pathogenic mutation (also known as p.T1378*), located in coding exon 10 of the BRCA2 gene, results from an in-frame TGAGGA insertion between nucleotide positions 4131 and 4132. This changes the amino acid from a threonine to a stop codon within coding exon 10. This mutation (designated as 4359ins6) has been previously reported in a pair of identical female twins with breast cancer (Delgado L et al. Cancer Genet. and Cytogenet. 2002 Feb;133:24-8). This alteration was identified in multiple large, worldwide studies of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Laitman Y et al. Hum Mutat. 2019 Nov;40(11):e1-e23; Santonocito C et al. Cancers (Basel). 2020 May 19;12(5):1286.). 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)
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Pathogenic
(Apr 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839934.1
First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016 |
Comment:
This c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene has been reported in multiple breast cancer and pancreatic cancer patients [PMID: 11890985, 25940717] while not observed … (more)
This c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene has been reported in multiple breast cancer and pancreatic cancer patients [PMID: 11890985, 25940717] while not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene is classified as pathogenic. (less)
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146378.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Uruguay
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Italian
Geographic origin: Canada
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Italian
Geographic origin: Uruguay
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American
Observation 6:
Number of individuals with the variant: 5
Ethnicity/Population group: Western European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Irish, Italian
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Next-generation sequencing of BRCA1 and BRCA2 genes for rapid detection of germline mutations in hereditary breast/ovarian cancer. | Nicolussi A | PeerJ | 2019 | PMID: 31065452 |
The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. | Schenkel LC | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27376475 |
Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. | Holter S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25940717 |
The molecular analysis of BRCA1 and BRCA2: Next-generation sequencing supersedes conventional approaches. | D'Argenio V | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25896959 |
Identification of a novel in-frame deletion in BRCA2 and analysis of variants of BRCA1/2 in Italian patients affected with hereditary breast and ovarian cancer. | Vietri MT | Clinical chemistry and laboratory medicine | 2012 | PMID: 23096105 |
Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. | Ding YC | Breast cancer research and treatment | 2011 | PMID: 20927582 |
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. | Palma MD | Cancer research | 2008 | PMID: 18703817 |
Hereditary breast cancer associated with a germline BRCA2 mutation in identical female twins with similar disease expression. | Delgado L | Cancer genetics and cytogenetics | 2002 | PMID: 11890985 |
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Text-mined citations for rs80359429 ...
HelpRecord last updated May 27, 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.