Variant classification summary

NM_000546.6:c.370T>C

TP53 · NP_000537.3:p.(Cys124Arg) · NM_000546.6

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

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Cys124Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.6:c.370T>C (p.Cys124Arg) is a missense variant in TP53 exon 4.

2

This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

3

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).

4

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.

5

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

6

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

7

The variant has been observed in somatic cancers (COSMIC COSV52752618, n=8).

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.

9

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

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 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).
PS1	Not met	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.	vcep_functional_worksheet
PS2	Not assessed	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.
PS3	Met	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.	vcep_functional_worksheet
PS4	Not assessed	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.
PS5	Not met	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.	vcep_functional_worksheet
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.	vcep_functional_worksheet
PM6	N/A	Not Applicable per TP53 VCEP; also prescreened as trivially not_applicable for this case.
PP1	Not assessed	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.
PP2	N/A	Not Applicable per TP53 VCEP.
PP3	Met	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.	vcep_pp3_bp4_codes bayesdel spliceai
PP4	Not assessed	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.
PP5	N/A	Not Applicable per TP53 VCEP; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not met	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.	vcep_functional_worksheet
BS4	Not assessed	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.
BP1	N/A	Not Applicable per TP53 VCEP.
BP2	N/A	Not Applicable per TP53 VCEP.
BP4	Not met	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.	vcep_pp3_bp4_codes bayesdel
BP5	N/A	Not Applicable per TP53 VCEP.
BP6	N/A	Not Applicable per TP53 VCEP.
BP7	N/A	BP7 applies only to synonymous (silent) or intronic variants. c.370T>C is a missense variant (p.Cys124Arg); BP7 is not applicable.

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