Variant classification summary

NM_000546.5:c.370T>A

TP53 · NP_000537.3:p.(Cys124Ser) · NM_000546.5

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

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

PP3 moderate BS3 strong BP6 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Cys124Ser)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.370T>A (p.Cys124Ser) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classified it as Likely Benign.

2

This variant is present at low frequency in gnomAD, including 3 of 1612186 alleles overall in v4.1 and 3 of 74876 alleles in the African/African American population; the subgroup frequency of 0.0000401 is slightly above the TP53 VCEP PM2 multi-allele threshold of less than 0.00004, so PM2 is not met.

3

In TP53 VCEP-supported functional datasets, p.Cys124Ser was functional in Kato et al. and showed no loss of function in the Giacomelli and Kotler datasets, supporting BS3.

4

In silico evidence is mixed: the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate to c.370T>A based on Align-GVGD class C65 and BayesDel 0.257897, while SpliceAI is 0.02 and predicts no meaningful splice effect; REVEL is 0.716.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -2, which maps to Likely Benign 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 variant is a missense change, p.(Cys124Ser), with SpliceAI max delta score 0.02, so it does not meet the TP53 null-variant or splice-disruption framework for PVS1.	pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart spliceai
PS1	Not assessed	No reviewed evidence was identified showing that a different nucleotide change causing the same p.(Cys124Ser) protein effect has already been classified as pathogenic or likely pathogenic under the TP53 VCEP rules.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with the phenotypic detail required for TP53 PS2 scoring was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application clinvar
PS3	Not met	Available TP53 functional evidence does not support a damaging effect. In the TP53 VCEP functional worksheet, p.(Cys124Ser) is listed as Functional in the Kato dataset and noLOF in the Giacomelli and Kotler datasets, so PS3 is not met.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965
PS4	Not met	No TP53 case-level PS4 point evidence was identified, and PM2_Supporting is not met because the highest gnomAD v4.1 African/African American frequency is 0.0000401 (3/74876), which is slightly above the TP53 VCEP multi-allele subgroup threshold of less than 0.00004.	cspec vcep_ps4_points_table gnomad_v4 clinvar
PM1	Not met	This missense variant is not at one of the TP53 VCEP hotspot codons 175, 245, 248, 249, 273, or 282, and Cancer Hotspots did not identify p.(Cys124Ser) as a statistically significant hotspot variant.	cspec hotspots
PM2	Not met	This variant is present in gnomAD. In v4.1, the highest observed frequency is 0.0000401 (3/74876) in the African/African American population, which is slightly above the TP53 VCEP multi-allele subgroup threshold of less than 0.00004 for PM2_Supporting, so PM2 is not met.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and the TP53 VCEP does not use PM4.	cspec
PM5	Not assessed	No reviewed evidence was identified showing that codon 124 has a different TP53 missense variant already classified as pathogenic or likely pathogenic under the TP53 VCEP rules at the level needed for PM5.	cspec clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified, so there is no evidence to score PP1.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application clinvar
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Met	The TP53 VCEP bioinformatic worksheet assigns PP3_Moderate to c.370T>A. This variant is listed as Align-GVGD class C65 with BayesDel 0.257897, which is above the TP53 PP3_Moderate BayesDel threshold of 0.16. SpliceAI is 0.02, indicating no predicted splice effect, and REVEL is 0.716.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No case-specific blood variant allele fraction data or constitutional mosaicism observations were identified to support TP53 PP4.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BA1	Not met	This variant does not meet BA1 because the highest observed gnomAD filtering allele frequency is far below the TP53 BA1 threshold of 0.001.	cspec gnomad_v4 gnomad_v2
BS1	Not met	This variant does not meet BS1 because the highest observed gnomAD filtering allele frequency is below the TP53 BS1 threshold of 0.0003.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No evidence was identified showing this variant in unrelated females aged 60 years or older without cancer from a single source, so BS2 cannot be assessed.	cspec
BS3	Met	In the TP53 VCEP functional worksheet, p.(Cys124Ser) is listed as Functional in Kato et al. and shows no loss of function in the Giacomelli and Kotler datasets. This pattern meets TP53 BS3 for retained function across eligible assays.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965
BS4	Not assessed	No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not applicable in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not applicable in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in the TP53 VCEP framework.	cspec
BP4	Not met	BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3_Moderate, not BP4, to c.370T>A. BayesDel is 0.257897, which is above the TP53 pathogenic threshold of 0.16, while SpliceAI is 0.02 and does not indicate a splice effect.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
BP5	N/A	BP5 is not applicable in the TP53 VCEP framework.	cspec
BP6	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 is a synonymous or intronic rule and is not applicable to this missense variant.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.