Classification rationale

PVS1PM5 Pathogenic

BRCA2 c.1924_1925insGG

The BRCA2 c.1924_1925insGG (p.(Ser642TrpfsTer3), p.(S642Wfs*3)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² This early frameshift predicts premature truncation of BRCA2, and the ENIGMA BRCA2 specification supports full PVS1 weight with additional PM5_Strong (PTC) applicability for truncating variants in exon 11.³ SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the ENIGMA PP3 splice threshold of 0.2 and supports a truncating rather than splice-altering mechanism.⁴

PVS1 + PM5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18

4 cspec ↗spliceai ↗

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 · 17 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

This variant is a frameshift change, NM_000059.4:c.1924_1925insGG, predicted to cause p.(Ser642TrpfsTer3) [p.(S642Wfs*3)] with truncation very early in BRCA2. The ENIGMA BRCA2 specification recognizes loss of function as an established disease mechanism, and the exon-level Table 4 assigns exon 11 truncating variants full PVS1 weight; available SpliceAI data do not suggest an alternative splice-driven explanation (max delta score 0.01).

Frameshift consequence p.(Ser642TrpfsTer3) / p.(S642Wfs*3)BRCA2 loss of function established in ENIGMA frameworkBRCA2 exon 11 Table 4 designation: PVS1

cspec ↗spliceai ↗

PM5 strong Pathogenic

This variant is a protein-truncating variant in BRCA2 exon 11. In the ENIGMA BRCA2 specification, PM5 is repurposed for truncating variants, and Table 4 shows that exon 11 is eligible for PM5_Strong (PTC), meaning a different proven pathogenic truncating variant has been established in this exon and additional pathogenic weight is allowed for another exon 11 truncating variant.

PM5 mode is PTC gene-specific rather than classic same-residue PM5BRCA2 exon 11 listed as PM5_Strong (PTC) applicable in Table 4

cspec ↗

Assessed · not applied · 7 not met · 10 not assessed

Pathogenic

PS1 Available evidence does not show that this variant has the same amino acid change or the same established splice effect as a previously classified pathogenic or likely pathogenic comparator.

PS3 No variant-specific calibrated functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table.

PS4 No case-control evidence or quantified excess of this variant in affected individuals versus controls was identified.

PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population databases.

PM3 No evidence was identified that this variant has been observed in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support PP3 under the BRCA2 ENIGMA rules.

PP4 No variant-specific multifactorial clinical-history likelihood ratio meeting BRCA2 ENIGMA thresholds was identified.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the BRCA2 ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BRCA2 ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01%.

BS2 No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would satisfy the ENIGMA point-based BS2 rule.

BS3 No variant-specific calibrated benign functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table.

BS4 No lack-of-segregation data were identified for this variant.

BP1 This variant is not a silent, missense, or in-frame change outside a clinically important functional domain.

BP4 Available computational evidence does not support BP4 for this variant under the BRCA2 ENIGMA rules.

BP5 No variant-specific multifactorial clinical-history likelihood ratio in the benign direction was identified for this allele.

BP7 This variant is not a silent or intronic change, and no RNA-only benign splicing evidence specific to this allele was identified.

N/A · 9 PS2 · PM1 · PM4 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6

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.

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 v4 ↗ gnomAD v2 ↗

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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

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

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

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

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

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

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