BRCA2 c.4005dup, p.Phe1336IlefsTer2
NM_000059.4:c.4005dup
Pathogenic
Using classification after pre-processing (Pathogenic) due to LLM failure: LLM response was not valid JSON even after cleaning: Expecting ':' delimiter: line 1 column 694 (char 693). Raw response snippet: {"final_classification":"Pathogenic","criteria_evaluation":[{"criterion":"PVS1","is_applied":true,"strength":"Very Strong","justification":"According to VCEP guidelines for PVS1: \"Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\" The evidence for this variant shows it is a frameshift insertion (F1336Ifs*2) predicted to introduce a premature stop codon and truncate critical functional domains of BRCA2. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP definition of a LOF variant in BRCA2.","},{"criterion":"PS1","is_applied":false,"strength":"Not Applied","justification":"According to VCEP guidelines for PS1: \"Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change...\" The evidence for this variant shows it is...
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.4005dup
Protein Change
F1336Ifs*2
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1336 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.4005dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The c.4005dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4005, causing a translational frameshift with a predicted alternate stop codon (p.F1336Ifs*2). This alteration has been reported in multiple large studies of BRCA1/2 mutation positive families (Tea MK et al. Maturitas, 2014 Jan;77:68-72; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). This alteration, designated 4232insA, has also been reported in a Hungarian male breast cancer patient (Ramus SJ et al. Am. J. Hum. Genet., 1997 May;60:1242-6). 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.
This sequence change creates a premature translational stop signal (p.Phe1336Ilefs*2) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 9150174, 24156927, 29446198, 29907814). This variant is also known as 4232insA. ClinVar contains an entry for this variant (Variation ID: 51581). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1336 in gene BRCA2
Functional Summary
The BRCA2 F1336Ifs*2 variant is a truncating mutation that results in the loss of critical protein domains, including the C-terminal DNA binding domain, nuclear localization signal, and CDK2 phosphorylation site. Functional studies indicate that such truncating mutations impair the nuclear localization of BRCA2, disrupting its role in maintaining homologous recombination during DNA damage response. This functional impairment supports a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PS3
PS3 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PM2
PM2 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
PP5
PP5 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)