LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-30
Case ID: NM_000546.6_c.-29_100dup_20260630_132018
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.6:c.-29+100dup

TP53  · NP_000537.3:p.?  · NM_000546.6
GRCh37: chr17:7590594 C>CT  ·  GRCh38: chr17:7687276 C>CT
Gene: TP53 Transcript: NM_000546.6
Final call
VUS
PM2 supporting BP4 supporting benign BP7 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.6
Protein
NP_000537.3:p.?
gnomAD AF
2.2591722392915236e-05 (v4.1)
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1 in TP53. SpliceAI predicts no splicing impact (max delta score = 0.00).
2
The variant is present in gnomAD v4.1 at an extremely low frequency (AF=2.26×10⁻⁵, 9/398,376 alleles; grpmax FAF=2.07×10⁻⁵), meeting PM2_Supporting per TP53 VCEP thresholds (total AF < 0.00003; subpopulation AF < 0.00004).
3
As an intronic variant outside the core splice motif with SpliceAI score ≤ 0.1, BP4_Supporting is met per the TP53 VCEP PP3/BP4/BP7 flowchart.
4
As an intronic variant at position +100 (beyond +7) with SpliceAI predicting no splice impact, BP7_Supporting is met per the TP53 VCEP specification (Walker et al. 2023, PMID:37352859).
5
The variant is absent from ClinVar and COSMIC and has not been reported in the literature. No proband, segregation, de novo, or functional data are available.
6
All other ACMG/AMP criteria are either not applicable (intronic variant outside scope of VCEP rules for missense/null/functional criteria) or not assessed due to absence of clinical data.
Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -1, which maps to VUS under the specified Tavtigian-style ranges.
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 NM_000546.6:c.-29+100dup is an intronic duplication at position +100 of intron 1, outside canonical splice sites (±1,2). The TP53 VCEP PVS1 flowchart covers null variants (nonsense, frameshift, canonical splice sites, CNVs) only. This intronic duplication does not fall under any PVS1 null-variant bucket.
pvs1_variant_assessment
PS1 N/A NM_000546.6:c.-29+100dup is an intronic duplication that does not alter the amino acid sequence. The TP53 VCEP PS1 rule applies only to variants producing the same amino acid change as an established pathogenic variant. Not applicable to a non-coding intronic variant.
PS2 Not assessed No de novo observation data are available for this variant. The TP53 VCEP PS2 rule requires proband points based on confirmed maternity/paternity and LFS-associated cancer types. No such evidence was identified in any source.
PS3 N/A The TP53 VCEP PS3 functional rule applies only to missense variants and small in-frame deletions assessed via protein function assays (Kato, Giacomelli, Kotler, Funk, Kawaguchi). NM_000546.6:c.-29+100dup is an intronic duplication, not amenable to these protein-level functional assays under the VCEP framework.
PS4 Not assessed No proband or case-control data are available for this variant. The TP53 VCEP PS4 rule requires point-based scoring of probands with LFS-associated cancers. No clinical cohort or case-control enrichment data were identified.
PS5 N/A PS5 is not a criterion defined in the ClinGen TP53 VCEP Specifications (v2.4.0). The VCEP does not include PS5 among its adjudicated criteria.
PM1 N/A The TP53 VCEP PM1 rule applies exclusively to missense variants at codons 175, 245, 248, 249, 273, or 282, or to germline missense variants with ≥2 somatic occurrences at cancerhotspots.org. NM_000546.6:c.-29+100dup is an intronic duplication and does not involve any of these codons.
PM2 Met This variant is present at an extremely low allele frequency in gnomAD v4.1 (total AF=2.26×10⁻⁵, 9/398,376 alleles), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003. The highest subpopulation frequency is in European (non-Finnish) at AF=3.98×10⁻⁵ (9/226,136 alleles), which is below the subpopulation threshold of 0.00004.
gnomad_v4
PM4 N/A The TP53 VCEP has designated PM4 as Not Applicable for this gene. The VCEP specifications v2.4.0 state PM4 is not applicable for TP53 variant interpretation.
cspec
PM5 N/A The TP53 VCEP PM5 rule applies exclusively to missense variants at an amino acid residue where pathogenic/likely pathogenic variants have been established. NM_000546.6:c.-29+100dup is an intronic duplication with no amino acid change (protein: p.?), and is not eligible for PM5 under the VCEP framework.
PM6 N/A The TP53 VCEP has designated PM6 as Not Applicable. The VCEP specifications v2.4.0 combine PM6 assessment under the PS2 de novo framework, and PM6 alone is not applied.
cspec
PP1 Not assessed No co-segregation data are available for this variant. The TP53 VCEP PP1 rule requires observed co-segregation in 3–4 meioses (supporting), 5–6 (moderate), or ≥7 (strong) across families. No family or segregation data were identified.
PP2 N/A The TP53 VCEP has designated PP2 as Not Applicable for this gene. PP2 requires a gene with low benign missense variation where missense variants are a common disease mechanism; the VCEP does not apply this criterion for TP53.
cspec
PP3 Not met The TP53 VCEP PP3 rule for intronic variants (excluding ±1,2) requires SpliceAI ≥ 0.2. For NM_000546.6:c.-29+100dup, SpliceAI max delta score is 0.00, which is well below the 0.2 threshold. No predicted splicing impact is present.
spliceai
PP4 Not assessed No phenotype or variant allele fraction (VAF) data are available for this variant. The TP53 VCEP PP4 rule requires observation of the variant with VAF 5–25% (moderate) or 5–35% (supporting). No clinical VAF data were identified.
PP5 N/A The TP53 VCEP has designated PP5 as Not Applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends against the use of this criterion.
cspec
BA1 Not met The TP53 VCEP BA1 threshold requires a filtering allele frequency (FAF) ≥ 0.001 (0.1%) in a gnomAD continental subpopulation (excluding founder populations). The grpmax FAF in gnomAD v4.1 is 2.07×10⁻⁵, far below the BA1 threshold. This variant is too rare to be considered a common benign polymorphism.
gnomad_v4
BS1 Not met The TP53 VCEP BS1 threshold requires FAF ≥ 0.0003 (0.03%) but < 0.001 in a gnomAD subpopulation with ≥2,000 alleles tested and ≥2 alleles present. The highest subpopulation AF in gnomAD v4.1 is European (non-Finnish) at 3.98×10⁻⁵ (0.004%), which is well below the 0.03% threshold.
gnomad_v4
BS2 Not assessed No data on unaffected elderly females carrying this variant are available. The TP53 VCEP BS2 rule requires ≥2 unrelated females who have reached ≥60 years of age without cancer from a single source. No such observations were identified.
BS3 N/A The TP53 VCEP BS3 functional rule applies only to missense variants and small in-frame deletions assessed via protein function assays (Kato, Giacomelli, et al.). NM_000546.6:c.-29+100dup is an intronic duplication and is not amenable to these protein-level functional assays under the VCEP framework.
BS4 Not assessed No segregation data in affected families are available for this variant. The TP53 VCEP BS4 rule requires lack of segregation in family members diagnosed with LFS-associated cancers. No family data were identified.
BP1 N/A The TP53 VCEP has designated BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in TP53.
cspec
BP2 N/A The TP53 VCEP has designated BP2 as Not Applicable for this gene.
cspec
BP3 N/A The TP53 VCEP has designated BP3 as Not Applicable. BP3 (in-frame deletion/insertion in a repetitive region without known function) does not apply to TP53 or to this intronic duplication variant.
cspec
BP4 Met NM_000546.6:c.-29+100dup is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP PP3/BP4/BP7 flowchart, intronic variants with SpliceAI ≤ 0.1 qualify for BP4_Supporting. SpliceAI max delta score for this variant is 0.00, satisfying this threshold.
spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5 N/A The TP53 VCEP has designated BP5 as Not Applicable. BP5 (variant found in a case with an alternate molecular basis for disease) is not applied under the TP53 VCEP framework.
cspec
BP6 N/A The TP53 VCEP has designated BP6 as Not Applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends against the use of this criterion.
cspec
BP7 Met NM_000546.6:c.-29+100dup is an intronic variant at position +100 of intron 1, which is beyond the +7 position. Per the TP53 VCEP BP7 rule, intronic variants at or beyond +7 to −21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1) qualify for BP7_Supporting. SpliceAI max delta score is 0.00, satisfying this criterion.
spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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