BRCA2c.9014_9015delPathogenic

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Variant interpretation report

BRCA2 c.9014_9015del, p.(Arg3005IlefsTer12)

NM_000059.4:c.9014_9015del NP_000050.3:p.(Arg3005IlefsTer12) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BRCA2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 strong (pathogenic)
Expert rules: ClinGen BRCA2 VCEP v1.2.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM5 (strong): 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.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen BRCA2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

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.

PM5Strong

PM5 · strong

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

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

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 2 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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.

SpliceAI predicts possible splice impact with a maximum delta score of 0.23.

Met · 2

PVS1 Very strongThis 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. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 PVS1 with exon-specific Table 4 guidance

Evidence considered

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.
ENIGMA Table 4 marks exon 23 truncating variants as PVS1.

Sources

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

PM5 StrongThis 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. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 PM5_PTC exon-specific Table 4 guidance

Evidence considered

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

Sources

cspec ↗vcep_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

Not met · 2 · evaluated, threshold not reached

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). BA1 is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 BA1

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.
BA1 threshold is FAF > 0.001.

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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. BS1 is not met. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 BS1

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.
BS1 thresholds are FAF > 0.00002 and FAF > 0.0001.

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not assessed · 9 · no assessment recorded

PS3 No variant-specific calibrated functional study supporting a damaging effect was identified for this deletion in the curated ENIGMA functional assay table. Available evidence does not support applying PS3 at this time. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 PS3

Evidence considered

No matching entry was identified for this variant in ENIGMA Table 9.

Still missing

No variant-specific calibrated protein functional assay result was identified.

Sources

cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8

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. Available evidence is insufficient to apply PS4. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 PS4

Evidence considered

ClinVar reports pathogenic submissions including ENIGMA expert panel review.
No qualifying PS4-specific dataset entry was identified in the reviewed ENIGMA supporting tables for this frameshift variant.

Still missing

No case-control study or proband-count dataset meeting ENIGMA PS4 requirements was identified.

Sources

clinvar ↗cspec ↗vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1

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. Available evidence does not support applying PM3. Details ▾Hide ▴

Rule

ENIGMA BRCA1/2 v1.2 PM3

Evidence considered

No PM3-eligible phenotype or trans observation was identified.

Still missing

No qualifying biallelic BRCA2 Fanconi anemia observation was identified.