Starting

Initialising…

BRCA2

Final classification

Pathogenic

BRCA2 c.9014_9015del · p.Arg3005IlefsTer12

BRCA2

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.

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.9014_9015del

Consequence

N/A

GRCh38

chr13:32379806 AAG>A

GRCh37

chr13:32953943 AAG>A

Basis ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 adapted ACMG/AMP criteria-combination rules) ▾

ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 adapted ACMG/AMP criteria-combination rules)

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 ↗

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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