Classification rationale

PVS1PM5 Pathogenic

BRCA2 c.7141_7147dup frameshift · exon 14

Pathogenic: PVS1 (very strong) is met for the exon 14 frameshift premature termination codon p.(Tyr2383SerfsTer11). Pathogenic: PM5 (strong) is met under ENIGMA Table 4 for a protein-termination codon in BRCA2 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.

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 11 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 at very strong: the BRCA2 exon 14 frameshift PTC p.(Tyr2383SerfsTer11) is pre-assigned PVS1 by ENIGMA Table 4 and lies before the c.9600 NMD boundary.

ENIGMA/ClinGen BRCA1 and BRCA2 VCEP specification v1.2 (cspec): PVS1 is a 'VERY STRONG' criterion applied at variable weight, with strength and description separated by variant type and applied 'according to PVS1 flowchart, which considers knowledge of clinically important functional domains'; for predicted protein-termination-codon (PTC) variants the code is applied 'with exon-specific weights derived for the PM5 (PTC) code', deferring to Specifications Table 4.Specifications Table 4 (ENIGMA BRCA2 exon-level PVS1 decision table): BRCA2 E14 row reads 'PVS1 | PTC | PM5_Strong (PTC)' - i.e. for a nonsense/frameshift variant whose PTC lies in exon 14 the pre-assigned PVS1 weight is full (very strong), and PM5_Strong (PTC) also applies. Table 4 notes that PVS1 weights were determined by the comprehensive decision trees in Appendices Section D, and that PM5 (PTC) weight is set by the exon where the termination codon occurs (may differ from the variant position).Specifications Table 4 exon map for BRCA2: exon 14 covers c.7008-c.7435 (p.2336-p.2479); the variant c.7141_7147dup and its PTC at codon 2393 (~c.7177) both lie inside exon 14.

cspec ↗

PM5 strong Pathogenic

Met at Strong: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) to BRCA2 exon 14 protein-termination variants, and this frameshift's stop codon falls in exon 14.

ENIGMA BRCA2 v1.2 Table 1, PM5_VariableWeight (PTC): 'Repurposing of PM5 code. Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before... Use to justify additional weight for PTC variants annotated as PVS1. Only applied to genomic PTC changes (not splicing). Weight determined by exon where the nucleotide change occurs. See Table 4, provided as a separate searchable excel file, for PM5 (PTC) codes applicable for predicted termination codon variants - organized by exon.'ENIGMA BRCA2 v1.2 Table 1, classic PM5 row: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before' - 'Do not use. Considered as component of bioinformatic analysis (PP3/BP4).'; corroborated by Appendix J Table 16 (PM5 = 'N/A. Some residues can harbor pathogenic and non-pathogenic substitutions.').Specifications Table 4 (BRCA2 sheet): exon 14 spans c.7008-c.7435 (p.2336_2479) and its PTC row reads 'PVS1 | PTC | PM5_Strong (PTC)'. The BRCA2 PM5_N/A exons are E6, E12 and E27; E14 is PM5_PTC-applicable.

cspec ↗

Assessed · not applied · 6 not met · 5 not assessed

Pathogenic

PS3 Not met: no variant-specific functional assay exists for c.7141_7147dup, and the governing ENIGMA Table 9 lists no PS3 entry for this allele.

PS4 Not assessed: no case-control dataset exists for this frameshift, and no declared PS4 table contains an entry for c.7141_7147dup (OR >= 4 required).

PM3 Not met: no Fanconi Anemia phenotype and no co-occurrent pathogenic BRCA2 allele in trans are reported, which the VCEP PM3_VariableWeight rule requires.

PP1 Not assessed: no pedigree or relative genotypes exist for this variant, so the ENIGMA-required quantitative co-segregation LR (PP1 threshold >= 2.08:1) cannot be computed.

PP4 Not assessed: no combined clinical likelihood ratio exists for this variant, and ENIGMA PP4 requires LR >= 2.08.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), far below the VCEP BA1 threshold of 0.001.

BS1 Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), below the VCEP BS1 threshold of 0.0001.

BS2 Not met: no genotype-positive probands were reported, so zero Table 8 points accrued toward the >= 1 point required for BS2_Supporting.

BS3 Not met: no functional assay of c.7141_7147dup was found reporting retained function, and the governing ENIGMA Table 9 lists no BS3 entry for this allele.

BS4 Not assessed: no family segregation data exist for this variant, so the ENIGMA-required co-segregation LR (BS4 supporting <= 0.48:1) cannot be computed.

BP5 Not assessed: no multifactorial clinical likelihood ratio exists for this variant, and ENIGMA BP5 requires LR <= 0.48.

N/A · 15 PS1 · PS2 · PM1 · PM2 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Rule & framework references · cited for criterion definitions, not variant evidence

10570174 ↗ Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

11239455 ↗ BRCA2 is required for homology-directed repair of chromosomal breaks.

20878484 ↗ A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.

22193408 ↗ BRCA1 and BRCA2: different roles in a common pathway of genome protection.

24312913 ↗ A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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