LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-07
Case ID: NM_000546.5_c.1031T_C_20260507_104422
Framework: ACMG/AMP 2015
Variant classification summary

NM_000546.5:c.1031T>C

TP53  · NP_000537.3:p.(Leu344Pro)  · NM_000546.5
GRCh37: chr17:7573996 A>G  ·  GRCh38: chr17:7670678 A>G
Gene: TP53 Transcript: NM_000546.5
Final call
Likely Pathogenic
PS3 strong PM2 supporting PP3 moderate PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.5
Protein
NP_000537.3:p.(Leu344Pro)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.1031T>C (p.Leu344Pro; p.L344P) variant has been observed in somatic cancer curation resources and has been reported in ClinVar, including a ClinGen TP53 Variant Curation Expert Panel likely pathogenic assertion.
2
This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07), with the highest observed population frequency in South Asian individuals of 1/91074 (AF 1.0980e-05), supporting rarity for TP53.
3
In TP53 functional studies summarized by the TP53 VCEP, p.Leu344Pro showed non-functional activity, loss-of-function behavior across eligible assays, and monomeric oligomerization-domain behavior, supporting a damaging loss-of-function effect.
4
Computational evidence is concordant with a damaging missense effect, with a TP53 VCEP pre-assigned PP3_moderate call, BayesDel 0.485604, and REVEL 0.862.
Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 8, which maps to Likely Pathogenic 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 This is a missense variant in the TP53 oligomerization domain and does not fall into the TP53 null-variant or canonical splice categories used for PVS1. Available evidence does not support a predicted loss-of-function mechanism through truncation or canonical splice disruption for this change.
cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1 Not assessed No independently verified evidence was identified showing a different nucleotide change that produces the same p.Leu344Pro amino acid substitution and has already been classified under the TP53 VCEP framework, so PS1 was not applied.
cspec clinvar
PS2 Not assessed No confirmed de novo occurrence with sufficient clinical and parental testing detail was identified, so PS2 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3 Met The TP53 VCEP functional worksheet assigns p.Leu344Pro to PS3 based on non-functional activity in the Kato framework, loss-of-function results across other eligible assays, and monomeric behavior in the oligomerization domain. Published functional studies for this variant support a damaging loss-of-function effect.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:9704930 PMID:19106109 PMID:19454241 PMID:20978130
PS4 Not assessed No verified TP53 VCEP point total from affected probands was identified for this variant, so PS4 was not applied.
cspec vcep_ps4_points_table
PM1 Not assessed This missense change is not one of the TP53 codons automatically eligible for PM1 under the VCEP specification, and a verified Cancer Hotspots count for the exact p.Leu344Pro substitution was not established from the retrieved evidence. PM1 was therefore not applied.
cspec hotspots
PM2 Met This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07). The highest observed ancestry-specific frequency is 1/91074 in South Asian individuals (AF 1.0980e-05), which is below the TP53 VCEP PM2 threshold of 0.00003 overall and below the 0.00004 ancestry threshold used when multiple alleles are present; PM2_Supporting is met.
cspec gnomad_v2 gnomad_v4
PM3 N/A PM3 is not applicable for the TP53 VCEP framework.
cspec
PM4 N/A PM4 is not applicable for the TP53 VCEP framework.
cspec
PM5 Not assessed A different missense change at codon 344 is present in ClinVar, but the retrieved evidence does not verify a qualifying TP53 VCEP pathogenic or clinically qualifying likely pathogenic comparison needed for PM5 application. PM5 was therefore not applied.
cspec clinvar
PM6 N/A PM6 is not applicable for the TP53 VCEP framework.
cspec
PP1 Not assessed No segregation data were identified showing this variant co-segregates with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A PP2 is not applicable for the TP53 VCEP framework.
cspec
PP3 Met The TP53 VCEP PP3/BP4 worksheet assigns c.1031T>C as PP3_moderate with aGVGD Class C65 and BayesDel 0.485604. Additional computational evidence is concordant, including a REVEL score of 0.862, supporting a damaging missense effect.
vcep_pp3_bp4_codes bayesdel revel cspec
PP4 Not assessed No case-level blood variant allele fraction or mosaicism data were identified to support TP53 VCEP PP4, so this criterion was not applied.
cspec
PP5 Met Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
cspec clinvar
BA1 Not met The observed population frequency does not reach the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group. gnomAD v4.1 shows only 1/1614076 alleles overall (AF 6.1955e-07), so BA1 is not met.
cspec gnomad_v4
BS1 Not met The observed population frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group. gnomAD v4.1 shows only 1/1614076 alleles overall (AF 6.1955e-07), so BS1 is not met.
cspec gnomad_v4
BS2 Not assessed No evidence was identified showing this variant in the number of unrelated cancer-free older females required for TP53 VCEP BS2, so this criterion was not applied.
cspec
BS3 Not met Available functional evidence does not show normal or near-normal TP53 function. Instead, the TP53 VCEP functional worksheet assigns this variant to PS3 based on non-functional and loss-of-function results, so BS3 is not met.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:9704930 PMID:19106109 PMID:19454241 PMID:20978130
BS4 Not assessed No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers, so BS4 was not applied.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1 N/A BP1 is not applicable for the TP53 VCEP framework.
cspec
BP2 N/A BP2 is not applicable for the TP53 VCEP framework.
cspec
BP3 N/A BP3 is not applicable for the TP53 VCEP framework.
cspec
BP4 Not met Computational evidence does not support a benign effect. The TP53 VCEP PP3/BP4 worksheet assigns PP3_moderate rather than BP4, BayesDel is 0.485604, and REVEL is 0.862, all of which are consistent with a damaging missense effect.
vcep_pp3_bp4_codes bayesdel revel cspec
BP5 N/A BP5 is not applicable for the TP53 VCEP framework.
cspec
BP6 N/A BP6 is not applicable for the TP53 VCEP framework.
cspec
BP7 N/A BP7 applies to synonymous or certain intronic variants without predicted splicing impact and is not applicable to this missense variant.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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