Variant classification summary

NM_000546.5:c.344A>G

TP53 · NP_000537.3:p.(His115Arg) · NM_000546.5

GRCh37: chr17:7579343 T>C · GRCh38: chr17:7676025 T>C

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Benign

BS3_Strong BP4_Supporting PM2_Supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(His115Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The TP53 c.344A>G (p.His115Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the ClinGen TP53 Variant Curation Expert Panel classifies it as Likely Benign.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 and supports rarity in population databases.

3

In TP53 functional studies summarized by the TP53 VCEP functional worksheet, p.His115Arg was functional in Kato data and showed no loss of function in Giacomelli and Kotler data, supporting BS3.

4

TP53-specific in silico assessment assigns BP4 because BayesDel is 0.0464313, below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03 below the 0.2 threshold; REVEL is 0.484.

Final determination: A total of -4 points under the TP53 VCEP Tavtigian framework supports a Likely Benign classification.

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 substitution, and available evidence does not indicate a nonsense, frameshift, canonical +/-1,2 splice, or other TP53 null-variant mechanism required for PVS1 application.	pvs1_gene_context pvs1_variant_assessment cspec vcep_pvs1_flowchart
PS1	Not assessed	No reviewed evidence identified an established TP53 VCEP Pathogenic or Likely Pathogenic variant that creates the same amino acid change, so PS1 was not assessed.	cspec clinvar
PS2	Not assessed	No confirmed de novo observations with appropriate parental confirmation were identified, so PS2 was not assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Available TP53 functional evidence does not support a damaging effect sufficient for PS3. The TP53 functional worksheet lists p.His115Arg as Functional in Kato data, with no loss of function in Giacomelli and Kotler data, and assigns a preliminary benign functional code instead of PS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965
PS4	Not assessed	No proband-based Li-Fraumeni syndrome point total was identified for this variant, so PS4 was not assessed.	cspec vcep_ps4_points_table gnomad_v2 gnomad_v4
PM1	Not met	This missense change is not at one of the TP53 codons predefined for PM1 application, and reviewed hotspot evidence did not show a statistically significant somatic hotspot or recurrent exact amino acid change count sufficient for TP53 PM1.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall allele frequency and supports rarity in population databases.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the TP53 VCEP framework for this disorder context.	cspec
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and the TP53 VCEP does not use PM4 in this context.	cspec
PM5	Not assessed	TP53 uses classic same-residue missense PM5 logic, but no validated previously classified pathogenic or likely pathogenic same-residue comparator was established from the reviewed materials, so PM5 was not assessed.	cspec pm5_candidates clinvar
PM6	N/A	PM6 is not applicable in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified to show cosegregation with Li-Fraumeni syndrome-associated cancers, so PP1 was not assessed.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not applicable in the TP53 VCEP framework.	cspec
PP3	Not met	Available computational evidence does not support a damaging prediction under TP53 VCEP rules. The TP53 PP3/BP4 worksheet assigns BP4 for c.344A>G, BayesDel is 0.0464313 which is below the TP53 PP3 threshold of 0.16, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03 below the 0.2 threshold. REVEL is 0.484 but TP53 VCEP PP3/BP4 uses BayesDel with splice review rather than REVEL for code assignment.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 bayesdel spliceai revel
PP4	Not assessed	No low-variant-allele-fraction constitutional mosaicism evidence or other qualifying TP53-specific phenotype data were identified, so PP4 was not assessed.	cspec
PP5	N/A	PP5 is not for use in the TP53 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 VCEP BA1 threshold of filtering allele frequency at or above 0.001.	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 VCEP BS1 threshold of filtering allele frequency at or above 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No single-source series of unaffected females age 60 years or older carrying this variant was identified, so BS2 was not assessed.	cspec
BS3	Met	Published TP53 functional evidence supports normal or near-normal protein function rather than loss of function. In the TP53 functional worksheet, p.His115Arg is listed as Functional in Kato data and noLOF in both Giacomelli and Kotler data, and the pre-assigned TP53 VCEP functional code is BS3.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:29979965
BS4	Not assessed	No lack-of-segregation data in affected relatives with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not assessed.	cspec
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 because this variant is not an in-frame indel in a repetitive region, and the TP53 VCEP does not use BP3 here.	cspec
BP4	Met	Available computational evidence supports a benign interpretation under TP53 VCEP rules. The TP53 PP3/BP4 worksheet assigns BP4 for c.344A>G, BayesDel is 0.0464313 which is below the TP53 PP3 threshold of 0.16 and within the BP4-supporting range, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.03 below the 0.2 threshold. REVEL is 0.484 and does not override the TP53 VCEP-specific BP4 assignment.	cspec 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 intended for synonymous or certain intronic variants and is not applicable to this missense substitution.	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.