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.1 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).2 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.3 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.4
BRCA2
Final classification
Likely Benign
BP1
BRCA2
c.3069_3074del
p.Asn1023_Ile1024del
This variant
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.
ENIGMA BRCA1/BRCA2 Table 3 framework (v1.2.0) applied. The sole met criterion is BP1_Strong: the variant is an in-frame deletion of two amino acids (p.Asn1023_Ile1024del) located outside the ENIGMA-defined clinically important functional domains (PALB2 binding domain aa 10-40; DNA binding domain aa 2481-3186), and SpliceAI max delta = 0.00 confirms no splicing impact. Under ENIGMA Table 3, a single Strong (Benign) criterion qualifies as Likely Benign when supported by multiple independent evidence types — satisfied here because BP1_Strong itself draws on two distinct evidence modalities: protein domain architecture and computational splicing prediction. No pathogenic criteria are met, so no conflicting-evidence point calculation is needed.
Classification rationale
BP1
Likely Benign
BRCA2 c.3069_3074del
BP1
→
Likely Benign
3
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_table4_v1_2_2024_11_18vcep_pmid_31853058_brca2_clinical_history_lr
4
cspec ↗
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP1
strong
Benign
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.
In-frame deletion at aa 1023-1024outside functional domains (aa 10-402481-3186). SpliceAI delta = 0.00 (≤0.1). Meets ENIGMA BP1_Strong criteria.
Assessed · not applied
· 14 not met · 0 not assessed
Pathogenic
PVS1
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).
PS3
Variant is not listed in ENIGMA Specifications Table 9 (calibrated functional assay results for BRCA2).
PS4
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).
PM2
ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer) in an outbred population.
PP1
ENIGMA PP1 requires quantitative co-segregation analysis with likelihood ratio ≥2.08:1 (Supporting), ≥4.3:1 (Moderate), or ≥18.7:1 (Strong).
PP3
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.
PP4
ENIGMA PP4 requires clinical-history likelihood ratio ≥2.08:1 from the Li et al.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (0.001) in gnomAD.
BS1
ENIGMA BS1_Supporting requires FAF >0.002% (0.00002) and BS1_Strong requires FAF >0.01% (0.0001).
BS2
ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, using a points-based system (Specifications Table 8).
BS3
Variant is not listed in ENIGMA Specifications Table 9 (calibrated functional assay results for BRCA2).
BS4
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).
BP4
ENIGMA BP4 applies to in-frame deletions inside a clinically important functional domain with BayesDel ≤0.18 and SpliceAI ≤0.1.
BP5
ENIGMA BP5 requires clinical-history likelihood ratio ≤0.48:1 from the Li et al.
N/A · 12
PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.3391e-06; MAF= 0.00043%, 7/1613238 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.33917e-05; MAF= 0.00534%, 4/74918 alleles, homozygotes = 0); grpmax FAF= 1.746e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.10172e-06; MAF= 0.00071%, 2/281622 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.06907e-05; MAF= 0.00807%, 2/24786 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 7 / 1,613,238
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
African/African American 4 / 74,918 |
0.0053% |
European (non-Finnish) 3 / 1,179,562 |
0.00025% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.00071%
· 2 / 281,622
0 hom
0 hom
African/African American 2 / 24,786 |
0.0081% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 182312)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
40664060 ↗
Characterization and functional analysis of BRCA1 and BRCA2 variants in a cohort of 100 unselected patients undergoing germline screening.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
27854360 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
CLINVAR
30287823 ↗
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.
CLINVAR