Variant classification summary

NM_000059.4:c.9014_9015del

BRCA2 · NP_000050.3:p.(Arg3005IlefsTer12) · NM_000059.4

GRCh37: chr13:32953943 AAG>A · GRCh38: chr13:32379806 AAG>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Arg3005IlefsTer12)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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

Final determination: Pathogenic based on one Very Strong pathogenic criterion and one Strong pathogenic criterion under the ENIGMA BRCA1/BRCA2 Table 3 combination rules.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	cspec pvs1_gene_context pvs1_variant_assessment 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
PM5	Met	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.	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
PS1	N/A	This variant is a frameshift deletion rather than a missense substitution or a same-splicing-event comparison, so the ENIGMA PS1 rule does not apply.	cspec
PS2	N/A	No de novo framework is used for BRCA1/2-related cancers in the ENIGMA specification, so PS2 is not applied.	cspec
PS3	Not assessed	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.	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	Not assessed	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.	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_8 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
PM1	N/A	The ENIGMA BRCA2 specification designates PM1 as not applicable because critical-domain information is incorporated into the bioinformatic framework rather than used as an independent criterion.	cspec
PM2	N/A	This variant is absent from gnomAD v2.1 and gnomAD v4.1, but the ENIGMA BRCA2 specification does not apply PM2_Supporting to insertion, deletion, or delins variants. Therefore PM2 is not applied for this deletion.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	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.	cspec
PM4	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
PM6	N/A	No de novo framework is used for BRCA1/2-related cancers in the ENIGMA specification, so PM6 is not applied.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
PP3	N/A	SpliceAI predicts possible splice impact with a maximum delta score of 0.23, which is above the ENIGMA PP3 splice threshold of 0.2. However, the ENIGMA BRCA2 specification states that PP3 should not be applied when PVS1 is met at any strength, so PP3 is not applied here.	spliceai cspec
PP4	Not assessed	No multifactorial likelihood ratio meeting ENIGMA thresholds was identified, so PP4 cannot be applied.	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_8 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
PP5	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified that this variant was observed under ENIGMA BS2 conditions, such as biallelic observation without Fanconi anemia features. Available evidence does not support applying BS2.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified for this deletion in the curated ENIGMA functional assay table. Available evidence does not support applying BS3.	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
BS4	Not assessed	No quantitative evidence showing lack of segregation with disease was identified, so BS4 cannot be applied.	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_8 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BP1	N/A	This variant is a frameshift deletion, not a silent, missense, or in-frame variant outside a clinically important domain, so BP1 does not apply.	cspec
BP2	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
BP3	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
BP4	N/A	This variant is not a missense, in-frame, silent, or non-canonical intronic variant eligible for BP4, and SpliceAI shows a maximum delta score of 0.23, which is above the BP4 splice threshold of 0.1. BP4 is not applicable.	spliceai cspec
BP5	Not assessed	No multifactorial likelihood ratio against pathogenicity meeting ENIGMA thresholds was identified, so BP5 cannot be applied.	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_8 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BP6	N/A	This criterion is not used in the ENIGMA BRCA2 specification.	cspec
BP7	N/A	This variant is a frameshift deletion rather than a silent or eligible intronic variant, so BP7 does not apply.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.