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TP53c.370T>CLikely pathogenic
Print report
Variant interpretation report

TP53 c.370T>C, p.(Cys124Arg)

NM_000546.6:c.370T>C NP_000537.3:p.(Cys124Arg) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong

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.

PM2Supporting
PM2 · supporting

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.

PP3Moderate
PP3 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely pathogenic.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
8 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 8 not met · 6 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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).

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.

SpliceAI predicts no significant splicing impact (max delta score 0.02), consistent with a missense effect rather than a splicing alteration.

This variant has been reported in ClinVar as Likely pathogenic by a single clinical laboratory (SCV006277400).

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.

No benign criteria are met. No evidence for BA1, BS1, BS2, BS3, BS4, or BP4 was identified.

Met · 3

PS3 StrongPer 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. Details ▾Hide ▴
Evidence considered
  • Kato assay: Non-functional
  • Giacomelli assay: LOF
  • Kotler assay: LOF
  • VCEP Functional-worksheet.xlsx pre-assigned code: PS3
Sources
vcep_functional_worksheet
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 ModeratePer 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. Details ▾Hide ▴
Evidence considered
  • aGVGD Class C65
  • BayesDel score: 0.25469
  • SpliceAI max delta: 0.02 (no predicted splicing impact)
  • VCEP PP3-BP4-codes.xlsx pre-assigned: PP3_moderate
Sources
vcep_pp3_bp4_codesbayesdelspliceai ↗

Not met · 8 · evaluated, threshold not reached

PS1 No other missense variant at codon 124 has been classified as Pathogenic or Likely Pathogenic per the TP53 VCEP specifications. Functional-worksheet variants at C124 (C124D=PS3_Supporting, C124S=BS3, etc.) do not meet the VCEP PS1 threshold of a prior Pathogenic or Likely Pathogenic classification. Details ▾Hide ▴
Evidence considered
  • VCEP Functional-worksheet.xlsx shows C124R is the only variant at codon 124 assigned PS3
  • other C124 variants have weaker or benign codes
  • none meet the PS1 comparator threshold.
Sources
vcep_functional_worksheet
PM1 Codon 124 is not among the VCEP-designated critical codons (175, 245, 248, 249, 273, 282) for PM1_moderate. Cancerhotspots.org does not list C124R with the requisite somatic occurrences for PM1_Supporting; the hotspots check returned residue_significant=false and exact_variant_listed=no. Details ▾Hide ▴
Evidence considered
  • Codon 124 is not a VCEP critical codon
  • Cancerhotspots.org: residue not significant
  • variant not listed
PM5 No different missense variant at codon 124 has been classified as Pathogenic or Likely Pathogenic per TP53 VCEP specifications. Other C124 variants in the Functional-worksheet include C124D (PS3_Supporting), C124S (BS3), C124F (BS3), C124W (BS3), C124Y (BS3), and C124G (No evidence) — none meet the VCEP PM5 threshold requiring a prior P/LP classification. Details ▾Hide ▴
Evidence considered
  • C124D = PS3_Supporting (not P/LP)
  • C124S/F/W/Y = BS3 (not P/LP)
  • C124G/A = No evidence
  • No VCEP P/LP comparator at codon 124
Sources
vcep_functional_worksheet
BA1 NM_000546.6:c.370T>C is absent from gnomAD. The allele frequency does not meet the VCEP BA1 stand-alone threshold of filtering allele frequency ≥ 0.001 (0.1%) in any continental subpopulation. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • AF = 0
  • does not meet BA1 threshold of FAF ≥ 0.001
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_000546.6:c.370T>C is absent from gnomAD. The allele frequency does not meet the VCEP BS1 threshold of filtering allele frequency ≥ 0.0003 (0.03%) in any continental subpopulation. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • AF = 0
  • does not meet BS1 threshold of FAF ≥ 0.0003
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Functional data for C124R demonstrates loss of function, not benign function. The VCEP Functional-worksheet.xlsx assigns PS3 (not BS3). Kato assay: Non-functional; Giacomelli: LOF; Kotler: LOF. This is contrary to BS3 which requires functional or partially functional Kato data with no LOF evidence. Details ▾Hide ▴
Evidence considered
  • Kato: Non-functional
  • Giacomelli: LOF
  • Kotler: LOF
  • VCEP assigns PS3
  • not BS3
Sources
vcep_functional_worksheet
BP4 BayesDel score for c.370T>C is 0.25469, which is above the BP4 threshold (> -0.008). The VCEP PP3-BP4-codes.xlsx assigns this variant PP3_moderate, not BP4. PP3 is met instead. Details ▾Hide ▴
Evidence considered
  • BayesDel score: 0.25469 (> -0.008 threshold for BP4)
  • VCEP assigns PP3_moderate
  • not BP4
Sources
vcep_pp3_bp4_codesbayesdel
PS5 PS5 relies on the same principle as PS1 — a different nucleotide change at the same codon resulting in a pathogenic classification. No other nucleotide change at codon 124 has been classified as Pathogenic or Likely Pathogenic per TP53 VCEP specifications. Details ▾Hide ▴
Evidence considered
  • Same analysis as PS1: no VCEP-classified P/LP comparator at codon 124.
Sources
vcep_functional_worksheet

Not assessed · 6 · no assessment recorded

PS2 No de novo observation data for NM_000546.6:c.370T>C was identified in the reviewed literature. None of the available full-text publications mention this variant. Details ▾Hide ▴
Still missing
  • No de novo data available
  • clinical testing reports may contain PS2-relevant observations that are not publicly accessible.
Sources
911558725741868203014881739238524493721
PS4 No proband case data with LFS cancer scoring was identified in the reviewed literature. None of the available publications describe clinical observations of NM_000546.6:c.370T>C in affected individuals. Details ▾Hide ▴
Still missing
  • No case-level proband data available
  • literature search did not identify variant-specific clinical observations.
Sources
911558725741868203014881739238524493721
PP1 No cosegregation data for NM_000546.6:c.370T>C was identified in the reviewed literature. None of the available publications describe familial segregation of this variant. Details ▾Hide ▴
Still missing
  • No segregation data available
  • family studies may exist but were not captured in the literature search.
Sources
911558725741868203014881739238524493721
PP4 No variant allele fraction (VAF) data from clinical testing is available to assess PP4. The VCEP PP4 rule requires observation with VAF 5-35%, which would require access to clinical testing reports not available in the current dataset. Details ▾Hide ▴
Still missing
  • No VAF data available from clinical testing
  • PP4 assessment requires access to clinical laboratory reports.
BS2 No data on unaffected females aged ≥ 60 years without cancer is available for this variant. The VCEP BS2 rule requires a specific count of such individuals from a single source. Details ▾Hide ▴
Still missing
  • No data on healthy elderly females
  • gnomAD absence suggests rarity but BS2 requires specific unaffected-aging-cohort data.
BS4 No segregation data demonstrating lack of segregation in affected family members is available for this variant. The VCEP BS4 rule requires observation of the variant in unaffected family members from families with LFS-associated cancers. Details ▾Hide ▴
Still missing
  • No segregation data available
  • family studies may exist but were not captured.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. The TP53 VCEP PVS1 flowchart applies only to null variants (nonsense, frameshift, canonical splice, initiation codon, and deletions). c.370T>C is a missense variant (p.Cys124Arg). Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPNot Applicable per TP53 VCEP; also prescreened as trivially not_applicable for this case. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPNot Applicable per TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPNot Applicable per TP53 VCEP; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPNot Applicable per TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPNot Applicable per TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPNot Applicable per TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPNot Applicable per TP53 VCEP. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. c.370T>C is a missense variant (p.Cys124Arg); BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TP53
Transcript
NM_000546.6
Coding (HGVS c.)
NM_000546.6:c.370T>C
Protein (HGVS p.)
NP_000537.3:p.(Cys124Arg)
GRCh38
chr17:7675999 A>G
GRCh37
chr17:7579317 A>G
ClinVar
4056245, 376680
COSMIC
COSV52752618

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.

TP53NM_000546.6
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +254 bp
0.000
SpliceAI acceptor gainat +69 bp
0.020
SpliceAI donor lossat +195 bp
0.020
SpliceAI donor gainat -114 bp
0.020
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.060

Other predictors

REVEL
0.883
BayesDel
0.255

How the predictions were used

PP3 ModeratePer 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. Details ▾Hide ▴
Evidence considered
  • aGVGD Class C65
  • BayesDel score: 0.25469
  • SpliceAI max delta: 0.02 (no predicted splicing impact)
  • VCEP PP3-BP4-codes.xlsx pre-assigned: PP3_moderate
Sources
vcep_pp3_bp4_codesbayesdelspliceai ↗
BP4 BayesDel score for c.370T>C is 0.25469, which is above the BP4 threshold (> -0.008). The VCEP PP3-BP4-codes.xlsx assigns this variant PP3_moderate, not BP4. PP3 is met instead. Details ▾Hide ▴
Evidence considered
  • BayesDel score: 0.25469 (> -0.008 threshold for BP4)
  • VCEP assigns PP3_moderate
  • not BP4
Sources
vcep_pp3_bp4_codesbayesdel
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. c.370T>C is a missense variant (p.Cys124Arg); BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.883. BayesDel score = 0.25469.

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Reappraisal of p53 mutations in human malignant astrocytic neoplasms by p53 functional assay: comparison with conventional structural analyses.
    No paper-specific finding is recorded.
    PMID 9115587 ↗
  • 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.
    Richards S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    No paper-specific finding is recorded.
    PMID 17392385 ↗
  • Li-Fraumeni Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301488 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    Lu KH et al. · 2014
    No paper-specific finding is recorded.
    PMID 24493721 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389258 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52752618, n = 8 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.