LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_000059.4_c.2988C_T_20261106_160059
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.2988C>T

BRCA2  · NP_000050.3:p.(Leu996=)  · NM_000059.4
GRCh37: chr13:32911480 C>T  ·  GRCh38: chr13:32337343 C>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.(Leu996=)
gnomAD AF
6.196815828154861e-07 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1, PM4, and BP3 are all not applicable under the ENIGMA BRCA2 VCEP rules because NM_000059.4:c.2988C>T is a synonymous exon 11 substitution with no protein-length change and is not an in-frame indel, stop-loss, null, or canonical splice-site variant.
2
PP3 is not_assessed because the VCEP-required SpliceAI >=0.2 value is unavailable.
3
BP4 is not_applicable because the synonymous variant is outside the VCEP's defined BRCA2 functional domains and is not intronic.
4
BP7 is not_assessed because its outside-domain RNA path requires a qualifying mRNA-only assay that is unavailable; its ordinary silent-variant path is limited to variants inside a functional domain with BP4 met.
Final determination: Under the ENIGMA BRCA2 VCEP Table 3, a VUS results because neither a pathogenic nor a benign combination rule is satisfied by the adjudicated criteria.
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: c.2988C>T is synonymous, whereas ENIGMA PVS1 applies to null or canonical splice-site variants in its decision tree.
cspec pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 Not assessed Not assessed: no SpliceAI score or VCEP-file entry establishes the same pathogenic splicing impact required for this synonymous variant.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: the VCEP explicitly prohibits PS2 because de novo occurrences are not calibrated for BRCA1/2-related cancers.
vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: the ENIGMA functional-assay table has no row for c.2988C>T, p.Leu996=, or p.L996= and no variant-specific damaging assay result is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
PS4 Not assessed Not assessed: no target-variant case-control counts, odds ratio, confidence interval, or p-value were available to test the ENIGMA PS4 thresholds.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967 PMID:12692171 PMID:17508274 PMID:20065170 PMID:26324357
PM1 N/A Not applicable: the BRCA2 VCEP explicitly marks PM1 Not Applicable, and residue 996 is outside its listed functional domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant is absent from both required non-cancer gnomAD datasets, but the VCEP-required regional average read depth of at least 25 is unavailable.
cspec gnomad_v2
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, co-occurring BRCA2 pathogenic variant, phase, or PM3 point assignment is documented for this variant.
cspec
PM4 N/A Not applicable: PM4 is restricted to in-frame length changes or stop-loss variants, while c.2988C>T preserves the Leu996 protein residue.
cspec pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: PM5 is limited by this VCEP to PTC variants with a different proven pathogenic PTC in the same exon, not synonymous variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: the VCEP explicitly prohibits PM6 because de novo occurrences are not calibrated for BRCA1/2-related cancers.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no quantitative co-segregation likelihood ratio or family-level segregation data is available for c.2988C>T.
vcep_specifications_v1_2_2024_11_18
PP2 N/A Not applicable: the BRCA2 VCEP explicitly marks PP2 Not Applicable, so no missense-mechanism evidence is assigned.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not assessed Not assessed: SpliceAI returned no score, so the ENIGMA >=0.2 predicted-splicing threshold cannot be evaluated.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no target-specific multifactorial clinical likelihood ratio was available for comparison with the ENIGMA PP4 threshold of LR >=2.08:1.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_humu_40_1557_s001 PMID:31131967 vcep_supplementarytables_v1_2_2024_11_18
PP5 N/A Not applicable: the ENIGMA BRCA2 specification explicitly states that PP5 should not be used.
cspec clinvar
BA1 Not assessed Not assessed: gnomAD v4.1 AF is 6.1968e-07, far below the 0.001 BA1 threshold, but required VCEP read-depth data are unavailable.
cspec gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: gnomAD v4.1 maximum AF is 8.4753e-07, below the 0.00002 BS1-supporting threshold, but required VCEP read-depth data are unavailable.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, but no qualifying healthy-adult observation or VCEP BS2 point-system data are available.
cspec gnomad_v4
BS3 Not assessed Not assessed: the ENIGMA functional-assay table has no row for c.2988C>T, p.Leu996=, or p.L996= and no variant-specific benign assay result is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
BS4 Not assessed Not assessed: no quantitative lack-of-segregation likelihood ratio or affected-family non-segregation data is available for c.2988C>T.
vcep_specifications_v1_2_2024_11_18
BP1 Not assessed Not assessed: residue 996 is outside listed domains, but the required SpliceAI ≤0.1 no-splicing condition is unavailable.
cspec vcep_specifications_v1_2_2024_11_18
BP2 N/A Not applicable: the ENIGMA BRCA2 specification says BP2 is not for use and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: BP3 is restricted to in-frame indels in nonfunctional repeats, whereas c.2988C>T is a synonymous single-nucleotide substitution.
cspec pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: p.Leu996 lies outside ENIGMA's aa 10-40 and aa 2481-3186 domains, so silent-variant BP4 does not apply.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no target-specific multifactorial LR was available to test the BP5 Supporting inequality LR <=0.48:1.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_humu_40_1557_s001 PMID:31131967 vcep_supplementarytables_v1_2_2024_11_18
BP6 N/A Not applicable: the ENIGMA BRCA2 specification explicitly states that BP6 should not be used.
cspec clinvar
BP7 Not assessed Not assessed: outside-domain BP7 requires a qualifying mRNA-only assay, but no such assay result is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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