NM_000546.5:c.1009C>T

TP53 · NP_000537.3:p.(Arg337Cys) · NM_000546.5

GRCh37: chr17:7574018 G>A · GRCh38: chr17:7670700 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Arg337Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The TP53 c.1009C>T (p.Arg337Cys) variant has been observed in somatic cancer resources and is reported in ClinVar with a Pathogenic expert-panel assertion.

This variant is absent from gnomAD v2.1 and is not observed in gnomAD v4.1 (0/1613822 alleles), which supports rarity under the TP53 PM2_Supporting threshold.

In the TP53 VCEP functional framework, published assay evidence compiled in the expert-panel worksheet shows p.Arg337Cys is non-functional or loss-of-function, with a PS3 assignment supporting a damaging effect on p53 activity.

For in silico evaluation, the TP53 VCEP bioinformatic worksheet assigns PP3 to this missense change; BayesDel is 0.316468, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00).

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	This is a missense variant, p.Arg337Cys, with no predicted splice effect (SpliceAI max delta score 0.00), so it does not meet the TP53 null-variant framework for PVS1.	pvs1_gene_context pvs1_variant_assessment spliceai cspec vcep_pvs1_flowchart
PS1	Not assessed	No verified evidence was identified showing that a different nucleotide change produces the same amino acid substitution and has already been classified as Pathogenic or Likely Pathogenic under the TP53 VCEP framework.	cspec clinvar
PS2	Not assessed	No confirmed de novo observation with sufficient clinical point scoring was identified for this variant, so PS2 cannot be applied from the available evidence.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application clinvar
PS3	Met	In the TP53 VCEP functional worksheet, p.Arg337Cys is assigned PS3. The compiled assay results list the variant as non-functional in Kato, loss-of-function in Giacomelli, and monomer in Kawaguchi, supporting a damaging effect on p53 function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:16007150
PS4	Not assessed	This variant is rare enough to satisfy the TP53 rarity gate for PS4 evaluation, but no verified proband-based Li-Fraumeni syndrome point total was identified, so PS4 cannot be applied from the current evidence.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PM1	Not met	p.Arg337Cys is not one of the TP53 codons with automatic PM1 application, and the available hotspot review did not verify the Cancer Hotspots evidence needed to use the alternative somatic-occurrence PM1 rule.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and has 0/1,613,822 alleles in gnomAD v4.1, which is below the TP53 PM2 threshold of less than 0.00003 overall and below the single-population threshold of less than 0.00004.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not used in the TP53 VCEP framework for this condition context.	cspec
PM4	N/A	PM4 is not used in the TP53 VCEP framework for this variant type and disease context.	cspec
PM5	Not assessed	No verified same-residue pathogenic or likely pathogenic comparator variant classified under the TP53 VCEP framework was confirmed for codon 337, so PM5 was not applied.	cspec pm5_candidates
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified that established cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 cannot be applied.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application clinvar
PP2	N/A	PP2 is not used in the TP53 VCEP framework.	cspec
PP3	Met	For the TP53 missense-specific in silico framework, the VCEP worksheet assigns PP3 to c.1009C>T (p.Arg337Cys). BayesDel is 0.316468, which is above the TP53 pathogenic threshold of 0.16, REVEL is 0.715, and SpliceAI shows no predicted splice impact (max delta score 0.00).	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel revel spliceai
PP4	Not assessed	No qualifying low-variant-allele-fraction blood observation or other TP53-specific PP4 data were identified, so PP4 cannot be applied.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BA1 threshold of at least 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD v2.1 and has an allele frequency of 0.0 in gnomAD v4.1, which is below the TP53 BS1 threshold of at least 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No source identified 2 or more unrelated women aged at least 60 years without cancer carrying this variant from a single dataset, so BS2 cannot be applied.	cspec
BS3	Not met	Available TP53 functional evidence does not support retained or partially retained p53 function. Instead, the VCEP functional worksheet assigns PS3 based on non-functional and loss-of-function results, so BS3 is not met.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:16007150
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be applied.	cspec
BP1	N/A	BP1 is not used in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not used in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not used in the TP53 VCEP framework.	cspec
BP4	Not met	BP4 is not met because the TP53 VCEP bioinformatic worksheet assigns PP3, not BP4, to p.Arg337Cys. BayesDel is 0.316468, which is above the pathogenic threshold of 0.16, although SpliceAI predicts no splice effect.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai
BP5	N/A	BP5 is not used in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not for use in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 is a synonymous or intronic splicing-related code and does not apply 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.