Variant classification summary

NM_000546.6:c.710T>C

TP53 · NP_000537.3:p.(Met237Thr) · NM_000546.6

GRCh37: chr17:7577571 A>G · GRCh38: chr17:7674253 A>G

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Met237Thr)

gnomAD AF

1.2393524135768578e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 population frequencies are below the TP53 VCEP thresholds.

2

PP3 moderate: the TP53 VCEP pre-assigns PP3_moderate for c.710T>C with C65 classification and BayesDel 0.516761.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 point-based framework, PM2 supporting contributes 1 point and PP3 moderate contributes 2 points; the total of 3 points maps to 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.710T>C is a missense variant, whereas the TP53 PVS1 decision tree covers null and canonical splice-site variants; SpliceAI maximum delta is 0.021.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet pvs1_variant_assessment spliceai
PS1	Not assessed	Not assessed: no qualifying previously pathogenic or likely pathogenic TP53 variant with the same p.Met237Thr amino-acid change was established.	cspec clinvar
PS2	Not assessed	Not assessed: no documented de novo observation, parental testing, or proband point assignment is available to determine the VCEP PS2 strength from 1 to >=8 points.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not assessed	Not assessed: the VCEP M237T row assigns No evidence, with Kato partially functional and only Funk showing loss of function among the available non-Kato assays.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
PS4	Not assessed	Not assessed: no proband phenotype or case-control estimate is available to calculate the VCEP's PS4 points or strength.	cspec vcep_ps4_points_table
PM1	Not met	Not met: p.Met237Thr is codon 237, not one of TP53’s six specified PM1 codons, and no cancerhotspots.org count of at least 10 is established.	cspec cosmic hotspots
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 1.23935e-06 and highest ancestry AF is 1.66739e-05, both below the VCEP PM2 thresholds.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the TP53 VCEP explicitly marks PM4 Not Applicable, so no protein-length-change evidence is assigned to this missense substitution.	cspec
PM5	Not assessed	Not assessed: the PM5 search found zero same-residue comparators, but retrieval failed with HTTP 429 and cannot exclude a qualifying p.Met237 variant.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP explicitly designates PM6 as Not Applicable for this interpretation.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation data or countable meioses are available against the VCEP thresholds of 3-4, 5-6, or >=7 meioses.	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 not applicable.	cspec
PP3	Met	Met at moderate strength: VCEP Supplementary Table S2 pre-assigns PP3_moderate for c.710T>C with BayesDel 0.516761 and C65 classification.	cspec vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
PP4	Not assessed	Not assessed: VAF observations needed for the VCEP's PP4 thresholds are unavailable, including whether one or two qualifying 5-35% observations exist.	cspec
PP5	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of PP5, regardless of external pathogenic assertions.	cspec
BA1	Not met	Not met: highest eligible-subpopulation AF is 1.66739e-05, below the VCEP BA1 threshold of 0.001, with only one observed variant allele.	cspec gnomad_v4
BS1	Not met	Not met: highest eligible-subpopulation AF is 1.66739e-05, below the VCEP BS1 lower threshold of 0.0003 and represented by only one variant allele.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying count of unrelated cancer-free females aged at least 60 from a single source is available.	cspec
BS3	Not assessed	Not assessed: the VCEP M237T row assigns No evidence, with Kato partially functional but Funk showing loss of function, so neither BS3 pathway is satisfied.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
BS4	Not assessed	Not assessed: no affected-family non-segregation data are available for the VCEP's strong BS4 requirement involving LFS-associated cancers.	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 TP53 disease-causing variants.	cspec
BP2	N/A	Not applicable: the TP53 VCEP specification marks BP2 as not applicable for this interpretation.	cspec
BP3	N/A	Not applicable: the TP53 VCEP explicitly marks BP3 Not Applicable, and p.(Met237Thr) is a missense substitution rather than a repetitive-region in-frame deletion.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: the VCEP excludes BP4 for missense variants classified C65, despite SpliceAI maximum delta 0.021 indicating no splice impact.	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 marks BP5 not applicable and supplies no usable BP5 strength rule.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of BP6, regardless of external benign assertions.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.710T>C is a missense change producing p.Met237Thr.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai

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