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NM_000059.4:7141_7147dup
· BRCA2
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2 · v1.2
0%
complete
Final classification
Pathogenic
PVS1PM5
BRCA2
7141_7147dup
unknown
Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

This loss-of-function BRCA2 change disrupts a tumor-suppressor protein required for homologous-recombination DNA repair and is relevant to hereditary breast and ovarian cancer susceptibility.

Transcript
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HGVS · transcript:coding
NM_000059.4:7141_7147dup
GRCh38
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GRCh37
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Pathogenic: PVS1 (very strong) plus PM5 (strong) satisfy the ENIGMA BRCA2 VCEP Table 3 combination rule.
Classification rationale
PVS1PM5 Pathogenic
BRCA2 7141_7147dup unknown

Pathogenic: PVS1 (very strong) is met for the exon 15 frameshift premature-termination codon expected to undergo nonsense-mediated decay. Pathogenic: PM5 (strong) is met under ENIGMA Table 4 for a premature-termination codon in exon 14.

PVS1 + PM5 → Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Applied criteria · 2 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met, very strong: exon-15 frameshift p.(Tyr2383SerfsTer11) truncates the predicted product at residue 2393 of 3419 and is expected to undergo NMD.
The normalized consequence is NM_000059.4:c.7141_7147dup, a duplication producing NM_000059.4(NP_000050.3):p.(Tyr2383SerfsTer11); the predicted protein ends at residue 2393 while the original ends at residue 3419.ENIGMA BRCA2 specification v1.2 states that null variants including nonsense and frameshift variants receive PVS1 according to the exon-organized PVS1 flowchart and Table 4.ENIGMA Table 4 lists BRCA2 exon 15 PTC variants as PVS1 and lists the exon-15 coding duplication category as PVS1; the variant lies within the exon-15 coding interval c.6938-c.7435.
cspec ↗
PM5 strong Pathogenic
Met, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 14, where c.7141_7147dup creates p.(Tyr2383SerfsTer11).
Mutalyzer normalization gives NM_000059.4:c.7141_7147dup and predicts p.(Tyr2383SerfsTer11), a premature termination after a frameshift.Specifications_Table4_V1.2_2024-11-18.xlsx.txt places BRCA2 c.7008-c.7435 in exon 14 and assigns the exon 14 PTC row PM5_Strong (PTC).The ENIGMA specification repurposes PM5 for PTC variants and directs use of exon-specific Table 4 weights; this is not classic same-residue missense PM5.
cspec ↗
Assessed · not applied · 0 not met · 13 not assessed
Pathogenic
PS3 Not assessed: no variant-specific calibrated functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence.
PS4 Not assessed: no variant-specific case-control p-value, OR, or confidence interval was available to evaluate the PS4 requirements p-value <=0.05 and OR >=4.
PM3 Not assessed: no Fanconi-anemia phenotype, chromosome-breakage result, or pathogenic BRCA2 co-occurring variant with phase information is documented for this duplication.
PP1 Not assessed: no affected-relative segregation data or quantitative likelihood ratio was available to reach the ENIGMA PP1 threshold of LR ≥2.08:1.
PP4 Not assessed: no variant-specific combined clinical LR was available for comparison with the PP4 Supporting threshold LR >=2.08.
PP5 Not assessed: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification was available to trigger PP5.
Benign
BA1 Not assessed: no variant-specific gnomAD FAF, coverage, or quality-filter data are available to compare with the VCEP threshold of >0.001.
BS1 Not assessed: no variant-specific gnomAD FAF is available to compare with the VCEP BS1 thresholds of >0.00002 to >0.0001.
BS2 Not assessed: no healthy-adult genotype/co-occurrence or Fanconi-anemia phenotype data are available to assign the VCEP point score.
BS3 Not assessed: no variant-specific calibrated benign functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence.
BS4 Not assessed: no affected-relative non-segregation data or quantitative likelihood ratio was available to reach the ENIGMA BS4 threshold of LR ≤0.48:1.
BP5 Not assessed: no variant-specific clinical LR was available for the BP5 Supporting inequality LR <=0.48.
BP6 Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification was available to trigger BP6.
N/A · 13 PS1 · PS2 · PM1 · PM2 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD 🇨🇦 ↗
ClinVar No data
No ClinVar submissions were recorded for this variant.
ClinVar ↗
In silico No data
No in-silico prediction was recorded for this variant.
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
4Sources
CSpec VCEP
ClinVar
OncoKB
COSMIC