NM_000546.6:c.370T>C (p.Cys124Arg) is a missense variant in TP53 exon 4. This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).1 Functional studies demonstrate that p.Cys124Arg is non-functional in the Kato transcriptional assay and shows loss of function in both the Giacomelli and Kotler assays, meeting the TP53 VCEP criteria for PS3 (Strong).2 In silico prediction tools support a deleterious effect: aGVGD Class C65, BayesDel score 0.25469, and REVEL score 0.883. The TP53 VCEP PP3-BP4-codes.xlsx assigns PP3_moderate.3 SpliceAI predicts no significant splicing impact (max delta score 0.02), consistent with a missense effect rather than a splicing alteration.4 This variant has been reported in ClinVar as Likely pathogenic by a single clinical laboratory (SCV006277400).5 The variant has been observed in somatic cancers (COSMIC COSV52752618, n=8). Applying the TP53 VCEP v2.4.0 Tavtigian point-based framework: PS3 (Strong) = +4, PM2_Supporting = +1, PP3_moderate = +2. Total points = +7 (range 6-9), consistent with Likely Pathogenic.6 No benign criteria are met. No evidence for BA1, BS1, BS2, BS3, BS4, or BP4 was identified.
TP53
Final classification
Likely Pathogenic
TP53 c.370T>C · p.Cys124Arg
TP53
NM_000546.6:c.370T>C (p.Cys124Arg) is a missense variant in TP53 exon 4.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) = 7 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PP3
Likely Pathogenic
TP53 c.370T>C
PS3 + PM2 + PP3
→
Likely Pathogenic
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
strong
Pathogenic
Per TP53 VCEP Functional-worksheet.xlsx, C124R is assigned PS3. The Kato functional assay (PMID:12826609) shows Non-functional activity, and both Giacomelli (PMID:30224644) and Kotler (PMID:29979965) assays demonstrate loss of function (LOF), representing a majority of available eligible assays. This satisfies the VCEP PS3 rule: Non-functional on Kato data AND LOF by the majority of other eligible assays.
Kato assay: Non-functionalGiacomelli assay: LOFKotler assay: LOF
✓
PM2
supporting
Pathogenic
NM_000546.6:c.370T>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). This meets the TP53 VCEP PM2_Supporting threshold of allele frequency < 0.00003 (0.003%). No population alleles are present in any genetic ancestry group.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)
✓
PP3
moderate
Pathogenic
Per TP53 VCEP PP3-BP4-codes.xlsx, c.370T>C (p.Cys124Arg) is assigned PP3_moderate. This variant has aGVGD Class C65 and BayesDel score 0.25469 (≥ 0.16), meeting the VCEP PP3_moderate threshold for missense variants. SpliceAI max delta score is 0.02 (< 0.2), indicating no predicted splicing impact.
aGVGD Class C65BayesDel score: 0.25469SpliceAI max delta: 0.02 (no predicted splicing impact)
Assessed · not applied
Pathogenic
PS1
No other missense variant at codon 124 has been classified as Pathogenic or Likely Pathogenic per the TP53 VCEP specifications.
PS2
No de novo observation data for NM_000546.6:c.370T>C was identified in the reviewed literature.
PS4
No proband case data with LFS cancer scoring was identified in the reviewed literature.
PM1
Codon 124 is not among the VCEP-designated critical codons (175, 245, 248, 249, 273, 282) for PM1_moderate.
PM5
No different missense variant at codon 124 has been classified as Pathogenic or Likely Pathogenic per TP53 VCEP specifications.
PP1
No cosegregation data for NM_000546.6:c.370T>C was identified in the reviewed literature.
PP4
No variant allele fraction (VAF) data from clinical testing is available to assess PP4.
Benign
BA1
NM_000546.6:c.370T>C is absent from gnomAD.
BS1
NM_000546.6:c.370T>C is absent from gnomAD.
BS2
No data on unaffected females aged ≥ 60 years without cancer is available for this variant.
BS3
Functional data for C124R demonstrates loss of function, not benign function.
BS4
No segregation data demonstrating lack of segregation in affected family members is available for this variant.
BP4
BayesDel score for c.370T>C is 0.25469, which is above the BP4 threshold (> -0.008).
N/A · 9
PVS1 · PM6 · PP2 · PP5 · BP1 · BP2 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 4056245)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.883. BayesDel score = 0.25469.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
9115587 ↗
Reappraisal of p53 mutations in human malignant astrocytic neoplasms by p53 functional assay: comparison with conventional structural analyses.
ONCOKB
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR