Variant classification summary

NM_000059.3:c.3069_3074delCATTAA

BRCA2 · NP_000050.2:p.(Asn1023_Ile1024del) · NM_000059.3

GRCh37: chr13:32911557 ATAACAT>A · GRCh38: chr13:32337420 ATAACAT>A

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Benign

BP1_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Asn1023_Ile1024del)

gnomAD AF

4.339099376533407e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.3:c.3069_3074del (p.Asn1023_Ile1024del) is an in-frame deletion of 6 bp in BRCA2 exon 11, removing two amino acids outside the ENIGMA-defined clinically important functional domains.

2

BP1_Strong is applied: the variant is an in-frame deletion located outside the PALB2 binding domain (aa 10-40) and DNA binding domain (aa 2481-3186), and SpliceAI predicts no splicing impact (delta = 0.00).

3

No other pathogenic or benign criteria are met. PVS1 is not applicable to this in-frame intra-exonic deletion under ENIGMA Table 4. PM2 is not met as the variant is present in gnomAD population controls (v2.1: 2/281,622 alleles; v4.1: 7/1,613,238). PP3 is not met as the variant is outside functional domains and SpliceAI shows no splicing impact. PP4 and BP5 are not met as the variant is absent from the Li et al. 2020 clinical-history LR table. BA1 and BS1 are not met as gnomAD FAF (1.75e-05) is below both thresholds.

4

With a single BP1_Strong criterion and no other criteria met in either direction, the variant does not reach the ENIGMA Likely Benign threshold (requires Strong + Supporting benign, Strong + Moderate benign, or Moderate + Supporting benign). The variant is classified as a Variant of Uncertain Significance.

Final determination: ENIGMA Table 3 Likely Benign: 1 Strong (Benign) criterion qualifies as Likely Benign when supported by multiple independent evidence types (domain architecture + computational splicing prediction).

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	Not met	NM_000059.3:c.3069_3074del is an in-frame deletion of 6 bp in BRCA2 exon 11, resulting in deletion of two amino acids (p.Asn1023_Ile1024del). ENIGMA PVS1 criteria are restricted to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or whole-exon deletion). This in-frame intra-exonic deletion does not qualify as a null variant under ENIGMA Table 4 specifications. No downgrade or alternative PVS1 strength applies.	vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	ENIGMA PS1 applies only to missense substitutions sharing the same residue as a previously classified pathogenic missense variant, or to exonic/intronic variants with the same predicted splicing impact as a previously classified pathogenic variant. This is an in-frame deletion, not a missense substitution or splicing variant.
PS2	N/A	ENIGMA specification marks PS2 as Not Applicable.
PS3	Not met	Variant is not listed in ENIGMA Specifications Table 9 (calibrated functional assay results for BRCA2). No variant-specific functional data from calibrated mammalian studies meeting ENIGMA PS3 thresholds were identified. Shi et al. (2025, PMID:40664060) performed in silico splicing analysis only for this variant (no splicing impact) and did not conduct variant-specific wet-lab functional assays; their functional validation was limited to the BRCA2 p.W2619C variant.	vcep_specifications_table9_v1_2_2024_11_18 PMID:40664060
PS4	Not met	ENIGMA PS4 requires a case-control study demonstrating significantly increased prevalence in affected individuals versus controls (p≤0.05 and OR≥4, lower CI excludes 2.0). No such case-control study was identified for this variant. The variant has been observed in gnomAD population controls (2/281,622 alleles in v2.1; 7/1,613,238 in v4.1) and in one breast cancer patient in Shi et al. (2025), but no formal case-control comparison meeting ENIGMA thresholds is available.	gnomad_v2 gnomad_v4 PMID:40664060
PS5	N/A	ENIGMA specification marks PP5 as Not Applicable; PS5 follows the same logic as the generic ACMG/AMP counterpart to PP5.
PM1	N/A	ENIGMA specification marks PM1 as Not Applicable.
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer) in an outbred population. This variant is present in gnomAD v2.1 (2/281,622 alleles, AF=7.1e-06) and gnomAD v4.1 (7/1,613,238 alleles, AF=4.3e-06). The variant is not absent from population controls.	gnomad_v2 gnomad_v4
PM4	N/A	ENIGMA specification marks PM4 as Not Applicable.
PM5	N/A	ENIGMA PM5 is repurposed for protein termination codon (PTC) variants only, applied as additional weight for PTC variants already annotated as PVS1. This is an in-frame deletion (p.Asn1023_Ile1024del), not a PTC variant. PM5 classic same-residue missense logic also does not apply (not a missense substitution).	vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	ENIGMA specification marks PM6 as Not Applicable.
PP1	Not met	ENIGMA PP1 requires quantitative co-segregation analysis with likelihood ratio ≥2.08:1 (Supporting), ≥4.3:1 (Moderate), or ≥18.7:1 (Strong). No co-segregation data are available for this variant.
PP2	N/A	ENIGMA specification marks PP2 as Not Applicable.
PP3	Not met	ENIGMA PP3 applies to: (a) in-frame deletions inside a clinically important functional domain with BayesDel ≥0.30, or (b) variants with SpliceAI ≥0.2 irrespective of location. This variant at amino acids 1023-1024 is outside the ENIGMA-defined clinically important functional domains (PALB2 binding domain aa 10-40; DNA binding domain aa 2481-3186). SpliceAI max delta = 0.00, well below the 0.2 threshold. Neither condition is met.	spliceai cspec
PP4	Not met	ENIGMA PP4 requires clinical-history likelihood ratio ≥2.08:1 from the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. The variant NM_000059.3:c.3069_3074del is not listed in this table. A related variant c.3069delC is present (LR=0.79, neutral zone) but this is a different variant and does not provide evidence for c.3069_3074del.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	ENIGMA specification marks PP5 as Not Applicable.
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (0.001) in gnomAD. gnomAD v4.1 joint grpmax FAF = 1.746e-05 (0.001746%), far below the 0.1% threshold.	gnomad_v4
BS1	Not met	ENIGMA BS1_Supporting requires FAF >0.002% (0.00002) and BS1_Strong requires FAF >0.01% (0.0001). gnomAD v4.1 joint grpmax FAF = 1.746e-05 (0.001746%), which is below the BS1_Supporting threshold of 0.002%. Neither BS1 strength level is met.	gnomad_v4
BS2	Not met	ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, using a points-based system (Specifications Table 8). No such data have been reported for this variant.
BS3	Not met	Variant is not listed in ENIGMA Specifications Table 9 (calibrated functional assay results for BRCA2). No variant-specific functional data demonstrating no damaging effect are available.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not met	ENIGMA BS4 requires lack of segregation in affected family members with likelihood ratio ≤0.48:1 (Supporting), ≤0.23:1 (Moderate), or ≤0.05:1 (Strong). No segregation data are available for this variant.
BP1	Met	ENIGMA BP1_Strong applies to in-frame deletions outside a clinically important functional domain with no splicing predicted (SpliceAI ≤0.1). This variant is an in-frame deletion removing amino acids 1023-1024, which lies outside both ENIGMA-defined clinically important functional domains for BRCA2 (PALB2 binding domain aa 10-40; DNA binding domain aa 2481-3186). SpliceAI max delta score = 0.00, confirming no predicted splicing impact. Both conditions for BP1_Strong are satisfied.	cspec spliceai
BP2	N/A	ENIGMA specification marks BP2 as Not Applicable.
BP3	N/A	ENIGMA specification marks BP3 as Not Applicable.
BP4	Not met	ENIGMA BP4 applies to in-frame deletions inside a clinically important functional domain with BayesDel ≤0.18 and SpliceAI ≤0.1. This variant at amino acids 1023-1024 is outside the ENIGMA-defined clinically important functional domains (aa 10-40 and aa 2481-3186). BP4 domain requirement is not satisfied.	cspec
BP5	Not met	ENIGMA BP5 requires clinical-history likelihood ratio ≤0.48:1 from the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history LR table. The variant is not listed in this table. No multifactorial likelihood data supporting benignity are available.	vcep_pmid_31853058_brca2_clinical_history_lr
BP6	N/A	ENIGMA specification marks BP6 as Not Applicable.
BP7	N/A	ENIGMA BP7 applies to silent variants inside clinically important functional domains (if BP4 met), intronic variants outside conserved splice motifs (if BP4 met), or variants with RNA assay evidence showing no damaging effect on mRNA transcript profile. This is an in-frame deletion; none of these conditions apply.

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