Classification rationale

PVS1PM5 Pathogenic

BRCA2 c.9014_9015del

The BRCA2 c.9014_9015del (p.Arg3005IlefsTer12) variant has not been observed in COSMIC and has been reported in ClinVar as pathogenic, including ENIGMA expert panel review.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, although ENIGMA does not apply PM2_Supporting to insertion, deletion, or delins variants.² ENIGMA BRCA2 null-variant guidance supports full-strength PVS1 for truncating variants in exon 23 and assigns PM5_PTC Strong to this exon, consistent with a deleterious premature termination event.³ SpliceAI predicts possible splice impact with a maximum delta score of 0.23.⁴

PVS1 + PM5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8

4 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 · 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

This variant is a frameshift deletion in BRCA2 that is predicted to introduce a premature termination codon, and BRCA2 loss of function is an established disease mechanism in the ENIGMA BRCA2 framework. The variant is in exon 23, where the ENIGMA exon-level null-variant table supports full-strength PVS1 for truncating variants.

BRCA2 loss of function is established in the ENIGMA BRCA2 specification.NM_000059.4:c.9014_9015del causes p.(Arg3005IlefsTer12).The variant maps to exon 23.

cspec ↗

PM5 strong Pathogenic

This protein-truncating variant occurs in BRCA2 exon 23, and the ENIGMA BRCA2 exon-level null-variant table assigns PM5_PTC Strong to exon 23. This supports additional pathogenic weight for a premature termination codon variant in an exon where pathogenic truncating variants have already been established.

The variant is a protein-truncating frameshift.The variant is in BRCA2 exon 23.ENIGMA Table 4 lists exon 23 as PM5_Strong (PTC).

cspec ↗

Assessed · not applied · 2 not met · 9 not assessed

Pathogenic

PS3 No variant-specific calibrated functional study supporting a damaging effect was identified for this deletion in the curated ENIGMA functional assay table.

PS4 This variant has been reported in ClinVar, including expert panel review, but no qualifying case-control statistic, odds ratio, or ENIGMA proband-count evidence was identified to support PS4.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in a patient with BRCA2-related Fanconi anemia.

PP1 No quantitative segregation data were identified for this variant, so PP1 cannot be applied.

PP4 No multifactorial likelihood ratio meeting ENIGMA thresholds was identified, so PP4 cannot be applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the ENIGMA BA1 threshold of filter allele frequency greater than 0.1% (FAF > 0.001).

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the ENIGMA BS1 thresholds of filter allele frequency above 0.002% (FAF > 0.00002) for BS1_Supporting or above 0.01% (FAF > 0.0001) for BS1.

BS2 No evidence was identified that this variant was observed under ENIGMA BS2 conditions, such as biallelic observation without Fanconi anemia features.

BS3 No variant-specific calibrated functional study showing no damaging effect was identified for this deletion in the curated ENIGMA functional assay table.

BS4 No quantitative evidence showing lack of segregation with disease was identified, so BS4 cannot be applied.

BP5 No multifactorial likelihood ratio against pathogenicity meeting ENIGMA thresholds was identified, so BP5 cannot be applied.

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.

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 has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.23).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

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

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