Variant classification summary

NM_000546.6:c.665C>T

TP53 · NP_000537.3:p.(Pro222Leu) · NM_000546.6

GRCh37: chr17:7578184 G>A · GRCh38: chr17:7674866 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

BS3 strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Pro222Leu)

gnomAD AF

1.1772213857754481e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS3 Strong: P222L is functional in Kato and shows no loss of function in all three available follow-up assays.

2

PM2 Supporting: gnomAD v4.1 total allele frequency is 1.17722e-05, below the TP53 VCEP threshold of 0.00003.

Final determination: Under the ClinGen TP53 VCEP Version 2.4 point-based framework, BS3 Strong (-4) plus PM2 Supporting (+1) yields -3 points, and no listed classification rule covers that total; therefore the call is VUS.

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	Not applicable: c.665C>T produces the missense substitution p.Pro222Leu, whereas the TP53 PVS1 flowchart governs null-variant consequences.	cspec vcep_pvs1_flowchart
PS1	Not assessed	Not assessed: no prior P222L variant established as pathogenic or likely pathogenic under the TP53 VCEP specifications is available.	cspec PMID:17724467 PMID:19336573
PS2	Not assessed	Not assessed: no documented de novo observation, parental testing, or qualifying PS2 point total is available for c.665C>T.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not met	Not met: the governing worksheet classifies P222L as Kato Functional with noLOF in Funk, Giacomelli, and Kotler, not as a loss-of-function result.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:17724467
PS4	Not assessed	Not assessed: no VCEP-eligible proband phenotype or PS4 point total is available to compare with the Supporting 1-1.5-point threshold.	cspec vcep_ps4_points_table PMID:17724467 PMID:19336573 PMID:12826609 PMID:17392385 PMID:20065170
PM1	Not met	Not met: Pro222 is outside the six VCEP PM1 codons, and cancerhotspots.org reports no qualifying hotspot occurrence for P222L.	cspec hotspots cosmic
PM2	Met	Met at supporting: gnomAD v4.1 total AF was 1.17722e-05, below the VCEP 0.00003 PM2 threshold, with South Asian AF 2.19568e-05 below 0.00004.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP specification marks PM3 as Not Applicable, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: p.Pro222Leu is a missense substitution, and the TP53 VCEP Version 2.4 CSPEC marks PM4 Not Applicable.	cspec
PM5	Not assessed	Not assessed: no different residue-222 missense variant with the required VCEP-established pathogenic or likely pathogenic status is documented.	cspec PMID:17724467 PMID:19336573
PM6	N/A	Not applicable: the TP53 VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative testing, family structure, or countable cosegregating meioses is documented for c.665C>T.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP explicitly marks PP2 as not applicable.	cspec
PP3	Not met	Not met: the VCEP table assigns c.665C>T "No evidence" with BayesDel class C0, despite a score of 0.224549, and SpliceAI max delta is 0.045.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PP4	Not assessed	Not assessed: no qualifying variant observation has a reported VAF within the VCEP PP4 5-35% range.	cspec PMID:17724467 PMID:19336573
PP5	N/A	Not applicable: the TP53 VCEP explicitly marks PP5 as Not Applicable.	cspec
BA1	Not met	Not met: highest eligible gnomAD v4.1 ancestry frequency was South Asian AF 2.19568e-05, below the 0.001 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: highest eligible gnomAD v4.1 ancestry-group FAF was 8.78e-06, below the 0.0003 BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying single-source count of unrelated cancer-free females aged at least 60 years was available.	cspec
BS3	Met	Met, Strong: P222L is Functional in Kato and noLOF in all three available follow-up assays, matching the VCEP's BS3 Strong rule.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609 PMID:17724467
BS4	Not assessed	Not assessed: no affected family members with LFS-associated cancers and discordant variant testing are documented for c.665C>T.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because truncating variants account for only a portion of disease-causing variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP specification marks BP2 as Not Applicable, regardless of cis/trans observations with another variant.	cspec
BP3	N/A	Not applicable: p.Pro222Leu is a missense substitution, and the TP53 VCEP Version 2.4 CSPEC marks BP3 Not Applicable.	cspec
BP4	Not met	Not met: BayesDel 0.224549 exceeds the VCEP BP4 supporting cutoff of <0.16, although SpliceAI max delta 0.045 is below 0.2.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
BP5	N/A	Not applicable: the TP53 VCEP explicitly marks BP5 as Not Applicable.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: c.665C>T is a missense variant producing p.Pro222Leu, whereas the VCEP BP7 rule covers only synonymous or intronic variants.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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