LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_000059.4_c.10043del_20261106_184812
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.10043del

BRCA2  · NP_000050.3:p.(Asn3348IlefsTer35)  · NM_000059.4
GRCh37: chr13:32972690 TA>T  ·  GRCh38: chr13:32398553 TA>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
VUS
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Asn3348IlefsTer35)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
All three requested computational criteria are not applicable because NM_000059.4:c.10043del is a frameshift and the ENIGMA BRCA2 PP3, BP4, and BP7 paths do not cover frameshift variants.
2
The variant was searched under c.10043del, p.Asn3348IlefsTer35, and p.N3348Ifs*35 in all four on-record VCEP full-text files; no variant-level entry was found.
Final determination: Under ENIGMA BRCA2 Table 3, no pathogenic or benign combination is satisfied when no adjudicated criterion is applied or met; the result is VUS.
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 N/A Not applicable: ENIGMA Table 4 assigns PVS1_N/A to BRCA2 exon 27 PTCs terminating after p.E3309, and this frameshift terminates at p.3382.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A Not applicable: the variant is a frameshift, while ENIGMA PS1 applies to missense substitutions or matched splicing events, not this consequence.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PS2 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific calibrated functional assay or ENIGMA Table 9 entry was found for c.10043del/p.Asn3348IlefsTer35.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4 Not assessed Not assessed: no variant-specific case-control counts, odds ratio, p-value, or confidence interval were available to evaluate the ENIGMA PS4 thresholds.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
PM1 N/A Not applicable: ENIGMA explicitly says PM1 should not be used for BRCA2, regardless of functional-domain location.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 N/A Not applicable: ENIGMA excludes deletion variants from PM2, and NM_000059.4:c.10043del is a deletion.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no Fanconi Anemia proband, co-occurrent pathogenic BRCA2 variant, or phase evidence is documented for the variant.
vcep_specifications_v1_2_2024_11_18 cspec
PM4 N/A Not applicable: ENIGMA says not to use PM4, which is limited to in-frame length changes or stop-loss variants, unlike this frameshift PTC.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: exon 27 PTC variants after p.E3309 receive PM5_N/A in ENIGMA Table 4, and this variant terminates at p.Ter3382.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PM6 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no variant-specific co-segregation LR or pedigree data are available to compare with the VCEP PP1 supporting threshold of LR >=2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA says PP2 should not be used, and this variant is a frameshift rather than a missense change.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: the frameshift is outside ENIGMA PP3 scope, which names missense, in-frame, silent, and qualifying intronic variants, despite SpliceAI 0.205.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment spliceai
PP4 Not assessed Not assessed: no variant-specific combined clinical likelihood ratio was available to compare with the ENIGMA PP4 threshold of LR ≥2.08.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331 PMID:31131967
PP5 N/A Not applicable: the ENIGMA VCEP explicitly states that PP5 is not for use.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: the variant was absent from gnomAD non-cancer searches, so its maximum filter allele frequency was not above the BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS1 Not met Not met: no gnomAD non-cancer allele was observed, so the maximum filter allele frequency did not exceed the BS1 threshold of 0.0001.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS2 Not assessed Not assessed: no eligible healthy-adult homozygote, heterozygote, or trans co-occurrence observation with the required phenotype and age context was available.
cspec vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no variant-specific calibrated functional assay or ENIGMA Table 9 entry was found for c.10043del/p.Asn3348IlefsTer35.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4 Not assessed Not assessed: no variant-specific non-segregation LR or affected-family data are available to compare with the VCEP BS4 supporting threshold of LR <=0.48 to >0.23:1.
cspec
BP1 N/A Not applicable: BP1 excludes frameshifts and also requires SpliceAI ≤0.1, whereas this variant has a maximum delta of 0.205.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the BRCA2 VCEP states BP2 is not to be used and limits it to the BS2 context.
vcep_specifications_v1_2_2024_11_18 cspec
BP3 N/A Not applicable: ENIGMA says not to use BP3, which is limited to in-frame changes in functionless repeats, not this frameshift PTC.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: BP4 covers missense/in-frame, silent, or qualifying intronic variants, whereas this variant is a frameshift with SpliceAI maximum delta 0.205.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment spliceai
BP5 Not assessed Not assessed: no variant-specific combined clinical likelihood ratio was available to test the ENIGMA BP5 Supporting inequality LR ≤0.48.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331 PMID:31131967
BP6 N/A Not applicable: the ENIGMA VCEP explicitly states that BP6 is not for use.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A Not applicable: BP7 requires a silent or qualifying intronic variant with BP4 met, but this variant is a frameshift and SpliceAI reaches 0.205.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment spliceai
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