Variant classification summary

NM_000546.5:c.370T>c

TP53 · NP_000537.3:p.(Cys124Arg) · NM_000546.5

GRCh37: chr17:7579317 A>G · GRCh38: chr17:7675999 A>G

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Cys124Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.5(NP_000537.3):c.370T>C (p.Cys124Arg) is a missense variant in exon 4 of TP53.

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2_Supporting per TP53 VCEP v2.4.0 (allele frequency <0.003%).

3

Functional studies demonstrate that p.Cys124Arg is non-functional in the Kato et al. assay and exhibits loss of function in the majority of other eligible assays (Giacomelli, Kotler), meeting PS3 at strong strength per TP53 VCEP specifications (Functional-worksheet.xlsx, Supplementary Table S3).

4

In silico predictors support a deleterious effect: aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, meeting PP3 at moderate strength per TP53 VCEP specifications (PP3-BP4-codes.xlsx, Supplementary Table S2). SpliceAI predicts no splicing impact (max delta 0.02).

5

The variant has been reported in ClinVar as Likely pathogenic by one clinical laboratory (ClinVar Variation ID: 4056245) and is observed in COSMIC with 8 somatic occurrences (COSV52752618).

6

No de novo observations, cosegregation data, proband phenotype scoring, or unaffected elderly carrier data were identified for this variant. PS2, PS4, PP1, PP4, BS2, and BS4 remain unassessed.

7

Applying the TP53 VCEP v2.4.0 Tavtigian point system: PS3 (+4) + PP3_Moderate (+2) + PM2_Supporting (+1) = +7 points, which falls in the Likely Pathogenic range (6-9 points).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 7, 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	PVS1 applies to null variants (nonsense, frameshift, canonical splice sites). NM_000546.5:c.370T>C is a missense variant (p.Cys124Arg) and does not fall into any PVS1 null-variant bucket per the TP53 VCEP PVS1 flowchart.	pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same codon producing the same amino acid change that has been classified as Pathogenic or Likely Pathogenic. p.Cys124Arg is produced by c.370T>C (TGT→CGT). No alternative nucleotide change at codon 124 can produce arginine, as the only Cys codons are TGT/TGC and the only Arg codon reachable via single-nucleotide substitution from these is CGT (via c.370T>C). No alternative nucleotide path exists.
PS2	Not assessed	No de novo observation with confirmed maternity/paternity was identified for this variant in any reviewed publication or database. The exploratory search suggested the IARC TP53 germline database as a potential source, but no confirmed de novo cases were retrieved.
PS3	Met	The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to p.Cys124Arg. Per VCEP rule: Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays qualifies for PS3 at strong strength. C124R is annotated as Non-functional on Kato data with LOF on Giacomelli and Kotler assays.	vcep_functional_worksheet
PS4	Not assessed	PS4 requires a significantly increased prevalence in affected individuals versus controls, scored by proband count and cancer type per the TP53 VCEP PS4 points table. No proband-specific data with cancer phenotypes was identified in the available evidence. The variant is reported in ClinVar (1 submitter, Likely pathogenic) and COSMIC (8 somatic occurrences), but these do not provide the proband-level germline clinical data needed for PS4 scoring.	clinvar
PS5	N/A	PS5 (PP5 equivalent) is designated as Not Applicable by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
PM1	Not met	Codon 124 is not among the six TP53 VCEP-designated PM1_Moderate codons (175, 245, 248, 249, 273, 282). The alternative PM1 rule requires the variant to be listed on cancerhotspots.org with ≥2 somatic occurrences for PM1_Supporting. The variant is not listed as a statistically significant hotspot on cancerhotspots.org (residue_significant: false, exact_variant_listed: no). Although COSMIC reports 8 somatic occurrences, cancerhotspots.org is the specific database referenced by the VCEP rule.
PM2	Met	The variant is absent from gnomAD v2.1 and v4.1, meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%). Absent from all population databases examined.	gnomad_v2 gnomad_v4
PM5	Not met	PM5 requires a different pathogenic or likely pathogenic missense variant at the same amino acid residue (Cys124) classified per TP53 VCEP specifications. The VCEP Functional-worksheet.xlsx shows other missense variants at codon 124 (C124D: PS3_Supporting; C124G: No evidence; C124S, C124W, C124Y, C124F: BS3), but none have been classified as Pathogenic or Likely Pathogenic by the VCEP. The pm5 candidate search found zero eligible comparator variants.	vcep_functional_worksheet pm5_candidates
PM6	N/A	PM6 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
PP1	Not assessed	No cosegregation data was identified in any reviewed publication. The TP53 VCEP requires 3-4 meioses for PP1_Supporting, 5-6 for PP1_Moderate, and ≥7 for PP1_Strong. No family studies with segregation data for this variant were found.
PP2	N/A	PP2 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
PP3	Met	The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.370T>C. Per VCEP rule: aGVGD Class C65 and BayesDel score ≥0.16 qualifies for PP3_moderate. The variant has aGVGD Class C65, BayesDel score 0.25469, REVEL score 0.883, and SpliceAI max delta 0.02 (no predicted splicing impact).	vcep_pp3_bp4_codes bayesdel revel spliceai
PP4	Not assessed	The TP53 VCEP PP4 criterion requires observation of the variant at low variant allele fraction (VAF 5-35%) indicating possible somatic mosaicism or clonal hematopoiesis. No VAF data was available for this variant in the provided evidence.
PP5	N/A	PP5 is designated as Not Applicable by the TP53 VCEP v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The TP53 VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in a non-founder gnomAD continental subpopulation with ≥2,000 alleles and ≥2 alleles present. The variant is absent from gnomAD v2.1 and v4.1. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The TP53 VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 but <0.001 in a non-founder gnomAD continental subpopulation. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	The TP53 VCEP BS2 rule requires observation in unrelated females ≥60 years without cancer (≥8 for Strong, 4-7 for Moderate, 2-3 for Supporting). No such data was identified for this variant.
BS3	Not met	BS3 requires well-established functional studies showing no deleterious effect. The TP53 VCEP Functional-worksheet.xlsx assigns PS3 (not BS3) to C124R, indicating loss of function across multiple functional assays (Non-functional on Kato, LOF on Giacomelli and Kotler). BS3 is contradicted by the available functional evidence.	vcep_functional_worksheet
BS4	Not assessed	BS4 requires lack of segregation in affected family members. No segregation data of any kind was identified for this variant. This criterion is typically difficult to assess for rare variants without dedicated family studies.
BP1	N/A	BP1 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
BP2	N/A	BP2 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
BP4	Not met	The TP53 VCEP BP4 rule requires BayesDel score <0.16 (Supporting: <0.16 and >-0.008; Moderate: ≤-0.008) AND no predicted splicing impact (SpliceAI <0.2). This variant has BayesDel score 0.25469 (≥0.16), aGVGD Class C65, and REVEL 0.883. These scores are in the pathogenic range and support PP3_moderate, not BP4. BP4 is not met.	bayesdel revel spliceai
BP5	N/A	BP5 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
BP6	N/A	BP6 is designated as Not Applicable by the TP53 VCEP v2.4.0.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants with no splicing impact. NM_000546.5:c.370T>C is a missense variant (p.Cys124Arg) and does not meet the variant type requirement for BP7.

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