Variant classification summary

NM_000546.6:c.659A>G

TP53 · NP_000537.3:p.(Tyr220Cys) · NM_000546.6

GRCh37: chr17:7578190 T>C · GRCh38: chr17:7674872 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Tyr220Cys)

gnomAD AF

4.956758478225579e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong is supported by non-functional Kato results and loss-of-function results in three additional assays.

2

Pathogenic: PM1 moderate is supported by 741 reported somatic occurrences of TP53 Y220C.

3

Pathogenic: PM2 supporting is supported by gnomAD allele frequencies below the TP53 VCEP thresholds.

4

Pathogenic: PP3 moderate is assigned by the VCEP for aGVGD C65 and BayesDel 0.562537.

5

Pathogenic: PP5 supporting reflects the ClinGen TP53 Expert Panel Pathogenic classification.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 point-based framework, PS3 strong (+4), PM1 moderate (+2), PM2 supporting (+1), PP3 moderate (+2), and PP5 supporting (+1) total 10 points, which maps to Pathogenic.

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.659A>G produces the missense substitution p.Tyr220Cys in exon 6, not a VCEP-specified null or splice variant.	cspec pvs1_variant_assessment vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not met	Not met: zero alternate missense comparator variants at TP53 residue 220 were identified for the required same-amino-acid comparison.	cspec pm5_candidates clinvar
PS2	Not assessed	Not assessed: no documented confirmed maternity, paternity, qualifying proband cancer, or de novo point total is available for the PS2 thresholds.	cspec clinvar vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	Met, strong: Y220C is non-functional in Kato and loss-of-function in all three available additional eligible assays, matching the VCEP PS3 strong rule.	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 counts are available to assign the VCEP's PS4 points or calculate enrichment for p.Tyr220Cys.	cspec vcep_ps4_points_table PMID:17508274
PM1	Met	Met at Moderate: TP53 Y220C has 741 reported somatic occurrences, exceeding the VCEP’s cancerhotspots.org threshold of at least 10.	cspec hotspots cosmic
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 4.95676e-06 and highest multi-allele ancestry AF is 5.93246e-06, both below VCEP thresholds.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP Version 2.4 CSPEC explicitly designates PM3 as Not Applicable.	cspec
PM4	N/A	Not applicable: p.Tyr220Cys is a missense substitution, not an in-frame insertion/deletion or stop-loss protein-length change.	cspec pvs1_variant_assessment
PM5	Not met	Not met: zero different missense variants at residue 220 were found for the VCEP’s required PM5 comparison.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP explicitly dropped PM6 and requires de novo evidence to be evaluated under PS2.	cspec
PP1	Not assessed	Not assessed: segregation is described in at least three families, but no exact qualifying meiosis count is available for the VCEP's 3-4, 5-6, or ≥7 thresholds.	cspec clinvar 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	Met	Met, moderate: the VCEP table assigns PP3_moderate to c.659A>G with aGVGD C65 and BayesDel 0.562537, while SpliceAI max delta is 0.135.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes bayesdel spliceai
PP4	Not assessed	Not assessed: no qualifying TP53 p.Tyr220Cys multigene-panel VAF observation is available for the VCEP's 5-35% PP4 rule.	cspec
PP5	Met	Not applicable: the TP53 VCEP explicitly prohibits use of PP5.	cspec clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 ancestry frequency is 1.56162e-05, far below the VCEP BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 joint grpmax FAF is 2.47e-06, below the VCEP BS1 lower threshold of 0.0003.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying single-source count of unrelated cancer-free females aged at least 60 years is available.	cspec gnomad_v4
BS3	Not met	Not met: Y220C is non-functional in Kato and loss-of-function in three additional available assays, rather than functional with no majority loss-of-function evidence.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:12826609
BS4	Not assessed	Not assessed: no affected family member with a documented negative variant test is available to demonstrate lack of segregation.	cspec
BP1	N/A	Not applicable: the TP53 VCEP explicitly excludes BP1 because truncating variants explain only part of TP53 disease causation.	cspec
BP2	N/A	Not applicable: the TP53 VCEP Version 2.4 CSPEC explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	Not applicable: c.659A>G is a missense substitution, not an in-frame deletion or insertion in a repetitive region without known function.	cspec pvs1_variant_assessment
BP4	Not met	Not met: the VCEP excludes aGVGD Class C65 from missense BP4, and this variant is Class C65 with BayesDel 0.562537 despite SpliceAI max delta 0.135.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes bayesdel spliceai
BP5	N/A	Not applicable: the TP53 VCEP marks BP5 as not applicable and provides no BP5 rule.	cspec
BP6	N/A	Not applicable: the TP53 VCEP explicitly prohibits use of BP6.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or intronic variants, whereas c.659A>G is a missense change encoding p.Tyr220Cys.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai

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