ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.3del (p.Met1fs)
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.3del (p.Met1fs)
Variation ID: 37872 Accession: VCV000037872.17
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32316463 (GRCh38) [ NCBI UCSC ] 13: 32890600 (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 1, 2014 Feb 20, 2024 Sep 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.3del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Met1fs frameshift initiator codon variant NM_000059.3:c.3delG NC_000013.11:g.32316463del NC_000013.10:g.32890600del NG_012772.3:g.5984del NG_017006.2:g.3901del LRG_293:g.5984del U43746.1:n.231delG - Protein change
- Other names
- 231delG
- Canonical SPDI
- NC_000013.11:32316462:G:
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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
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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
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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 |
18542 | 18699 |
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 (3) |
criteria provided, single submitter
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Oct 2, 2015 | RCV000031453.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2017 | RCV000574323.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2023 | RCV001380087.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2022 | RCV002288524.7 |
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
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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 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: SCV000326953.5
First in ClinVar: Sep 27, 2014 Last updated: Sep 03, 2023 |
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Pathogenic
(Apr 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002578988.2
First in ClinVar: Oct 15, 2022 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Mar 16, 2017)
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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: SCV000661417.5
First in ClinVar: Jan 01, 2018 Last updated: Sep 03, 2023 |
Comment:
The c.3delG pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide (G) at nucleotide position 3. … (more)
The c.3delG pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide (G) at nucleotide position 3. This alters the methionine residue at the initiation codon (p.M1?). While this specific alteration has not been reported in the literature to date, several other missense mutations (c.2T>G, c.3G>A, and c.2T>C) that alter the methionine residue at the initiation codon in BRCA2 (p.M1?) have been reported in breast and/or ovarian cancer families (Santos C et al. J Mol Diagn 2014 May;16(3):324-34; Thomassen M, Breast Cancer Res. Treat. 2012 Apr; 132(3):1009-23; Jakubowska, A et al. Eur J Hum Genet. 2003 Dec;11(12):955-8; Ambry internal data). Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, the c.3delG alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 03, 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: SCV001578032.5
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine is located at codon 124. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with colorectal cancer (PMID: 14647210, 18182601, 21769658, 24156927, 25330149, 29478780; Invitae). ClinVar contains an entry for this variant (Variation ID: 37872). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the N-terminal part of the BRCA2 protein that interacts with PALB2 (residues 18-40), which is critical for BRCA2-mediated homologous recombinational DNA repair (PMID: 16793542, 22678057, 19369211). This variant disrupts the p.Met1 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647210, 18182601, 21769658, 24156927, 25330149; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
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Pathogenic
(Dec 23, 2003)
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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: SCV000146001.2
First in ClinVar: Apr 01, 2014 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Pathogenic
(Jan 26, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000054058.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2023 |
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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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Inherited DNA-Repair Defects in Colorectal Cancer. | AlDubayan SH | American journal of human genetics | 2018 | PMID: 29478780 |
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. | Cybulski C | Clinical genetics | 2015 | PMID: 25330149 |
Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity. | Parsons MT | Molecular carcinogenesis | 2015 | PMID: 24302565 |
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. | Tea MK | Maturitas | 2014 | PMID: 24156927 |
Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. | Biswas K | Human molecular genetics | 2012 | PMID: 22678057 |
Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. | Thomassen M | Breast cancer research and treatment | 2012 | PMID: 21769658 |
PALB2 is an integral component of the BRCA complex required for homologous recombination repair. | Sy SM | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19369211 |
Variation of breast cancer risk among BRCA1/2 carriers. | Begg CB | JAMA | 2008 | PMID: 18182601 |
Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. | Xia B | Molecular cell | 2006 | PMID: 16793542 |
A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. | Jakubowska A | European journal of human genetics : EJHG | 2003 | PMID: 14647210 |
Text-mined citations for rs80359418 ...
HelpRecord last updated Apr 20, 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.