Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.4037_4038del (p.Thr1346fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Apr 2016 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.4037_4038del (p.Thr1346fs)
Variation ID: 51584 Accession: VCV000051584.49
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 13q13.1 13: 32338392-32338393 (GRCh38) [ NCBI UCSC ] 13: 32912529-32912530 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 1, 2014 Sep 16, 2024 Apr 22, 2016 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000059.4:c.4037_4038del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Thr1346fs frameshift NM_000059.3:c.4037_4038delCT NC_000013.11:g.32338392_32338393del NC_000013.10:g.32912529_32912530del NG_012772.3:g.27913_27914del LRG_293:g.27913_27914del U43746.1:n.4265_4266delCT - Protein change
- -
- Other names
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4265_4266delCT
4265delCT
- Canonical SPDI
- NC_000013.11:32338391:CT:
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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. |
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| BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18967 | 19126 | |
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 (7) |
reviewed by expert panel
|
Apr 22, 2016 | RCV000077318.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2023 | RCV000568203.16 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2024 | RCV000478122.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 9, 2024 | RCV001193778.17 | |
| Pathogenic (2) |
criteria provided, single submitter
|
May 15, 2023 | RCV001090055.11 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 22, 2016)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000282386.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
|
|
Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000326962.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(May 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216143.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226532.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP5, PM2, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000661155.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.4037_4038delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4037 to … (more)
The c.4037_4038delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4037 to 4038, causing a translational frameshift with a predicted alternate stop codon (p.T1346Sfs*5). This mutation has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome, and is commonly described as a founder mutation in the Filipino and Malay populations (Wagner T et al. Genomics 1999 Dec;62(3):369-76; De Leon Matsuda ML et al Int. J. Cancer 2002 Apr;98(4):596-603; Thirthagiri E et al Breast Cancer Res. 2008 Jul;10(4):R59; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). Of note, this alteration is also designated as 4265delCT in published literature. 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
(Jan 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199081.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
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Pathogenic
(Aug 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000564774.6
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and has been described as a Filipino founder variant (PMID: 10615237, 10644434, 11920621, 15131399, 18627636); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4265delCT and 4265_4266delCT; This variant is associated with the following publications: (PMID: 30350268, 30078507, 10644434, 18627636, 11920621, 26187060, 17591843, 12442265, 23364291, 10615237, 15131399, 28993434, 24578176, 34645131, 37937776, 33558524, 33461583, 29922827, 36385461, 32341426, 37310942) (less)
|
|
|
Pathogenic
(Jul 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362886.2
First in ClinVar: Jun 22, 2020 Last updated: Sep 16, 2024 |
Comment:
Variant summary: BRCA2 c.4037_4038delCT (p.Thr1346SerfsX5), also known as 4265delCT, results in a premature termination codon, predicted to cause a truncation of the encoded protein or … (more)
Variant summary: BRCA2 c.4037_4038delCT (p.Thr1346SerfsX5), also known as 4265delCT, 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4037_4038delCT has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, De Leon Matsuda_2002, Thirthagiri_2008, Li_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11920621, 30078507, 18627636). ClinVar contains an entry for this variant (Variation ID: 51584). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489032.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600572.3
First in ClinVar: Sep 28, 2017 Last updated: Dec 31, 2022 |
Comment:
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer … (more)
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 30078507 (2018), 28993434 (2018), 26187060 (2015), 18627636 (2008), 17591843 (2007), 11920621 (2002), 10644434 (1999)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001584853.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Thr1346Serfs*5) 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.Thr1346Serfs*5) 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 BRCA2-related conditions (PMID: 10644434, 11920621, 28993434, 30078507, 30350268, 32341426, 33558524). This variant is also known as 4265delCT. ClinVar contains an entry for this variant (Variation ID: 51584). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001344938.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least eight individuals affected with breast and/or ovarian cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 10615237, 10644434, 11920621, 15131399, 18627636, 28993434, 30078507, 30350268, 32341426, 33558524). Haplotype analysis among Filipino carriers affected with breast cancer suggests that this variant may be a founder mutation in this population (PMID: 11920621). 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)
|
|
|
Pathogenic
(Jun 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848393.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Thr1346SerfsX5 variant in BRCA2 has been identified in at least 11 individuals with BRCA2-related cancers (Johannsson 1999, De Leon Matsuda 2002,Lubinski 2014, Thirthagiri 2008, … (more)
The p.Thr1346SerfsX5 variant in BRCA2 has been identified in at least 11 individuals with BRCA2-related cancers (Johannsson 1999, De Leon Matsuda 2002,Lubinski 2014, Thirthagiri 2008, Li 2018, Wen 2018, Ryu 2019). This variant has been identified in 1/65954 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). This variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate. (less)
|
|
|
Pathogenic
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000146359.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Geographic origin: Sweden
Observation 2:
Number of individuals with the variant: 3
Ethnicity/Population group: Filipino
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Malay
Geographic origin: Malaysia
|
|
|
Pathogenic
(Aug 01, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000109115.3
First in ClinVar: Dec 23, 2013 Last updated: Jun 24, 2016 |
|
|
|
Pathogenic
(Apr 08, 2020)
|
no assertion criteria provided
Method: research
|
Familial breast cancer
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV000987244.3
First in ClinVar: Mar 01, 2020 Last updated: May 12, 2020 |
Comment:
ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr1346Serfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRCA2_REPEAT (F1421-1454P … (more)
ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr1346Serfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRCA2_REPEAT (F1421-1454P aa) domain, which, with other 39 aa repeats participates in RAD51 binding (a key protein in DNA recombinational repair) and confers resistance to methyl methanesulphonate treatment. This frameshift variant disrupts the function of the downstream domains which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1) (PP5 Pathogenic Supporting). In our study this variant was found in a 53-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. (less)
Age: 50-59 years
Sex: female
|
|
|
Pathogenic
(Mar 02, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV004243618.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Likely pathogenic
(Jul 21, 2023)
|
no assertion criteria provided
Method: research
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
deCODE genetics, Amgen
Accession: SCV004022165.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000059.4:c.4037_4038del (chr13:32338391) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar … (more)
The variant NM_000059.4:c.4037_4038del (chr13:32338391) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 1
Ethnicity/Population group: Icelandic
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Comment:
Comment:
PP5, PM2, PVS1
Comment:
The c.4037_4038delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4037 to 4038, causing a translational frameshift with a predicted alternate stop codon (p.T1346Sfs*5). This mutation has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome, and is commonly described as a founder mutation in the Filipino and Malay populations (Wagner T et al. Genomics 1999 Dec;62(3):369-76; De Leon Matsuda ML et al Int. J. Cancer 2002 Apr;98(4):596-603; Thirthagiri E et al Breast Cancer Res. 2008 Jul;10(4):R59; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). Of note, this alteration is also designated as 4265delCT in published literature. 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:
Frameshift 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and has been described as a Filipino founder variant (PMID: 10615237, 10644434, 11920621, 15131399, 18627636); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4265delCT and 4265_4266delCT; This variant is associated with the following publications: (PMID: 30350268, 30078507, 10644434, 18627636, 11920621, 26187060, 17591843, 12442265, 23364291, 10615237, 15131399, 28993434, 24578176, 34645131, 37937776, 33558524, 33461583, 29922827, 36385461, 32341426, 37310942)
Comment:
Variant summary: BRCA2 c.4037_4038delCT (p.Thr1346SerfsX5), also known as 4265delCT, 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4037_4038delCT has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, De Leon Matsuda_2002, Thirthagiri_2008, Li_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11920621, 30078507, 18627636). ClinVar contains an entry for this variant (Variation ID: 51584). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 30078507 (2018), 28993434 (2018), 26187060 (2015), 18627636 (2008), 17591843 (2007), 11920621 (2002), 10644434 (1999)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Thr1346Serfs*5) 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 BRCA2-related conditions (PMID: 10644434, 11920621, 28993434, 30078507, 30350268, 32341426, 33558524). This variant is also known as 4265delCT. ClinVar contains an entry for this variant (Variation ID: 51584). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least eight individuals affected with breast and/or ovarian cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 10615237, 10644434, 11920621, 15131399, 18627636, 28993434, 30078507, 30350268, 32341426, 33558524). Haplotype analysis among Filipino carriers affected with breast cancer suggests that this variant may be a founder mutation in this population (PMID: 11920621). 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.
Comment:
The p.Thr1346SerfsX5 variant in BRCA2 has been identified in at least 11 individuals with BRCA2-related cancers (Johannsson 1999, De Leon Matsuda 2002,Lubinski 2014, Thirthagiri 2008, Li 2018, Wen 2018, Ryu 2019). This variant has been identified in 1/65954 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). This variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate.
Comment:
ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr1346Serfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRCA2_REPEAT (F1421-1454P aa) domain, which, with other 39 aa repeats participates in RAD51 binding (a key protein in DNA recombinational repair) and confers resistance to methyl methanesulphonate treatment. This frameshift variant disrupts the function of the downstream domains which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1) (PP5 Pathogenic Supporting). In our study this variant was found in a 53-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.
Comment:
The variant NM_000059.4:c.4037_4038del (chr13:32338391) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely 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:
Variant allele predicted to encode a truncated non-functional protein.
Comment:
PP5, PM2, PVS1
Comment:
The c.4037_4038delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4037 to 4038, causing a translational frameshift with a predicted alternate stop codon (p.T1346Sfs*5). This mutation has been reported in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome, and is commonly described as a founder mutation in the Filipino and Malay populations (Wagner T et al. Genomics 1999 Dec;62(3):369-76; De Leon Matsuda ML et al Int. J. Cancer 2002 Apr;98(4):596-603; Thirthagiri E et al Breast Cancer Res. 2008 Jul;10(4):R59; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). Of note, this alteration is also designated as 4265delCT in published literature. 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:
Frameshift 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and has been described as a Filipino founder variant (PMID: 10615237, 10644434, 11920621, 15131399, 18627636); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4265delCT and 4265_4266delCT; This variant is associated with the following publications: (PMID: 30350268, 30078507, 10644434, 18627636, 11920621, 26187060, 17591843, 12442265, 23364291, 10615237, 15131399, 28993434, 24578176, 34645131, 37937776, 33558524, 33461583, 29922827, 36385461, 32341426, 37310942)
Comment:
Variant summary: BRCA2 c.4037_4038delCT (p.Thr1346SerfsX5), also known as 4265delCT, 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4037_4038delCT has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, De Leon Matsuda_2002, Thirthagiri_2008, Li_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11920621, 30078507, 18627636). ClinVar contains an entry for this variant (Variation ID: 51584). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 30078507 (2018), 28993434 (2018), 26187060 (2015), 18627636 (2008), 17591843 (2007), 11920621 (2002), 10644434 (1999)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Thr1346Serfs*5) 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 BRCA2-related conditions (PMID: 10644434, 11920621, 28993434, 30078507, 30350268, 32341426, 33558524). This variant is also known as 4265delCT. ClinVar contains an entry for this variant (Variation ID: 51584). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least eight individuals affected with breast and/or ovarian cancer and in additional suspected hereditary breast and ovarian cancer families (PMID: 10615237, 10644434, 11920621, 15131399, 18627636, 28993434, 30078507, 30350268, 32341426, 33558524). Haplotype analysis among Filipino carriers affected with breast cancer suggests that this variant may be a founder mutation in this population (PMID: 11920621). 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.
Comment:
The p.Thr1346SerfsX5 variant in BRCA2 has been identified in at least 11 individuals with BRCA2-related cancers (Johannsson 1999, De Leon Matsuda 2002,Lubinski 2014, Thirthagiri 2008, Li 2018, Wen 2018, Ryu 2019). This variant has been identified in 1/65954 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). This variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate.
Comment:
ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr1346Serfs is a known pathogenic variant in exon 11 in a non-functional domain just before the BRCA2_REPEAT (F1421-1454P aa) domain, which, with other 39 aa repeats participates in RAD51 binding (a key protein in DNA recombinational repair) and confers resistance to methyl methanesulphonate treatment. This frameshift variant disrupts the function of the downstream domains which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282386.1) (PP5 Pathogenic Supporting). In our study this variant was found in a 53-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.
Comment:
The variant NM_000059.4:c.4037_4038del (chr13:32338391) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer. | Moradian MM | Human genome variation | 2021 | PMID: 33558524 |
| Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
| Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea. | Ryu JM | Breast cancer research and treatment | 2019 | PMID: 30350268 |
| BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. | Li A | Gynecologic oncology | 2018 | PMID: 30078507 |
| Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. | Wen WX | Journal of medical genetics | 2018 | PMID: 28993434 |
| Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. | Kwong A | Journal of medical genetics | 2016 | PMID: 26187060 |
| Recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history. | Kang PC | Breast cancer research and treatment | 2014 | PMID: 24578176 |
| 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 |
| Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. | Thirthagiri E | Breast cancer research : BCR | 2008 | PMID: 18627636 |
| Founder mutations in BRCA1 and BRCA2 genes. | Ferla R | Annals of oncology : official journal of the European Society for Medical Oncology | 2007 | PMID: 17591843 |
| Cancer variation associated with the position of the mutation in the BRCA2 gene. | Lubinski J | Familial cancer | 2004 | PMID: 15131399 |
| BRCA1 and BRCA2 mutations among breast cancer patients from the Philippines. | De Leon Matsuda ML | International journal of cancer | 2002 | PMID: 11920621 |
| Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. | Wagner T | Genomics | 1999 | PMID: 10644434 |
| Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers. | Johannsson O | European journal of cancer (Oxford, England : 1990) | 1999 | PMID: 10615237 |
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Record last updated Nov 03, 2024
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