Variant classification summary

NM_000546.5:c.1010G>C

TP53 · NP_000537.3:p.(Arg337Pro) · NM_000546.5

GRCh37: chr17:7574017 C>G · GRCh38: chr17:7670699 C>G

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.(Arg337Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.1010G>C (p.Arg337Pro) variant has been observed in somatic cancers in COSMIC (6 occurrences) and has been reported in ClinVar as Likely Pathogenic with expert-panel review.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold.

3

In the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato dataset and loss-of-function in the Giacomelli framework, supporting a damaging effect on TP53 protein function and PS3.

4

Computational evidence is also consistent with a damaging missense effect: the TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C, BayesDel is 0.407328, REVEL is 0.792, and SpliceAI predicts no significant splice impact with a maximum delta score of 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, and available evidence does not indicate a nonsense, frameshift, canonical +/-1 or 2 splice, or other TP53 null-variant mechanism required for PVS1 application.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart
PS1	Not assessed	No evidence was identified showing that a different nucleotide change causing the same p.Arg337Pro amino acid substitution has already been classified by the TP53 VCEP at the strength required for PS1.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with the phenotype-specific TP53 point framework was identified, so PS2 cannot be applied from the currently reviewed evidence.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application PMID:10864200
PS3	Met	In the TP53 VCEP functional worksheet, p.Arg337Pro is listed as non-functional in the Kato transactivation dataset and loss-of-function in the Giacomelli assay framework, with a preliminary TP53 VCEP assignment of PS3, supporting a damaging effect on protein function.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
PS4	Not assessed	Although this variant has been reported in ClinVar and in somatic cancers, no proband-level Li-Fraumeni syndrome point total was identified from the reviewed evidence, so PS4 cannot be assigned.	cspec clinvar vcep_ps4_points_table PMID:10719737 PMID:10864200
PM1	Not met	p.Arg337Pro is not in the TP53 codons specified for PM1_Moderate, and the reviewed evidence did not establish exact Cancer Hotspots support required to apply PM1_Supporting for this amino acid change.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall allele frequency and supports PM2 at the supporting level.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable for TP53 in this VCEP framework.	cspec
PM4	N/A	PM4 is not applicable because this is not a protein length-changing variant and TP53 VCEP does not use PM4 for this context.	cspec
PM5	Not assessed	No reviewed source established that one or more different missense variants at codon 337 had already been classified by the TP53 VCEP at the strengths required for PM5.	cspec clinvar
PM6	N/A	PM6 is not applicable for TP53 in this VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified showing cosegregation of this variant with TP53-associated cancers across the meiosis counts required for PP1.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable for TP53 in this VCEP framework.	cspec
PP3	Met	The TP53 VCEP PP3/BP4 worksheet assigns PP3 to c.1010G>C based on Align-GVGD class C25 and BayesDel score 0.407328. SpliceAI predicts no splice effect with a maximum delta score of 0.00, and REVEL is high at 0.792, which is consistent with a damaging missense prediction.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No validated low variant-allele-fraction observation in blood or qualifying mosaicism-style evidence was identified, so PP4 cannot be applied from the reviewed evidence.	cspec
PP5	Met	Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BA1 threshold of at least 0.001 filtering allele frequency in a qualifying ancestry group.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 threshold of at least 0.0003 filtering allele frequency in a qualifying ancestry group.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No single-source dataset was identified showing the number of unrelated females aged 60 years or older without cancer required to apply BS2.	cspec
BS3	Not met	Available functional evidence does not support retained or partially retained TP53 function. Instead, the TP53 VCEP functional worksheet lists p.Arg337Pro as non-functional in Kato and loss-of-function in Giacomelli, which argues against BS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with TP53-associated cancers, so BS4 cannot be assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	BP1 is not applicable for TP53 in this VCEP framework.	cspec
BP2	N/A	BP2 is not applicable for TP53 in this VCEP framework.	cspec
BP3	N/A	BP3 is not applicable because this is not an in-frame indel in a repetitive region and TP53 VCEP does not use BP3 here.	cspec
BP4	Not met	Available computational evidence does not support BP4. The TP53 VCEP PP3/BP4 worksheet assigns PP3 rather than BP4 to c.1010G>C, with BayesDel 0.407328, Align-GVGD class C25, and SpliceAI max delta 0.00.	vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai
BP5	N/A	BP5 is not applicable for TP53 in this VCEP framework.	cspec
BP6	N/A	BP6 is not used in the TP53 VCEP framework.	cspec
BP7	N/A	BP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic 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.