Variant classification summary

NM_000546.5:c.1031T>G

TP53 · NP_000537.3:p.(Leu344Arg) · NM_000546.5

GRCh37: chr17:7573996 A>C · GRCh38: chr17:7670678 A>C

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PS3 strong PM1 supporting PM2 supporting PP3 moderate PP5 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Leu344Arg)

gnomAD AF

ClinVar

Likely Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: TP53 VCEP functional data show absent reporter activity and abnormal oligomerization for L344R.

2

PM1 supporting: p.Leu344Arg has 7 same-amino-acid-change hotspot occurrences.

3

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

4

PP3 moderate: the TP53 VCEP lookup table assigns PP3 moderate based on BayesDel class C65 and score 0.288212.

5

PP5 supporting: the ClinVar TP53 Expert Panel classifies the exact variant as Likely Pathogenic.

Final determination: The TP53 VCEP Version 2.4 point-based framework assigns 4 points for PS3 strong, 1 each for PM1, PM2, and PP5 supporting, and 2 for PP3 moderate; 9 total points maps to Likely 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.1031T>G is a missense substitution retaining the 393-amino-acid protein, outside the TP53 VCEP PVS1 null-variant rules.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: no independent pathogenic same-amino-acid-change comparator is available for L344R, and the variant's own ClinVar classification cannot supply PS1 evidence.	cspec
PS2	Not assessed	Not assessed: no documented parental testing, confirmed de novo status, proband cancer type, or PS2 point total is available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Met	Met, strong: the TP53 VCEP worksheet assigns PS3 to L344R, supported by absent reporter activity and a 98.2% ± 1.7% monomer fraction.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:19454241 PMID:16007150 PMID:20978130
PS4	Not assessed	Not assessed: no proband phenotype or per-proband PS4 point total is available to compare with the Supporting threshold of 1-1.5 points.	cspec vcep_ps4_points_table
PM1	Met	Met at Supporting: p.Leu344Arg has 7 same-amino-acid-change hotspot occurrences, within the VCEP's 2-9 occurrence threshold.	cspec PMID:20978130
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with frequency 0 versus the TP53 PM2 threshold of <0.00003.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: TP53 VCEP PM4 is not applicable, and p.Leu344Arg is a missense substitution with no protein-length change.	cspec
PM5	Not assessed	Not assessed: L344Q, L344P, and L344M have functional data, but no alternate L344 missense variant has the VCEP-required pathogenic adjudication and qualifying clinical evidence.	cspec pm5_candidates PMID:12826609 PMID:16007150
PM6	N/A	Not applicable: the TP53 VCEP dropped PM6 and requires all de novo evidence to be evaluated exclusively under PS2.	cspec
PP1	Not assessed	Not assessed: no documented affected relatives, cosegregation observations, or countable meioses are available for comparison with the 3-4 meioses supporting threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the governing TP53 VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Met	Met at moderate: the TP53 VCEP lookup table directly assigns PP3_moderate to c.1031T>G with BayesDel 0.288212 and SpliceAI 0.01.	cspec vcep_pp3_bp4_codes spliceai bayesdel
PP4	Not assessed	Not assessed: no independent PP4-eligible observation or variant allele fraction is reported for this variant.	cspec
PP5	Met	Met, supporting: the exact ClinVar expert-panel classification is Likely Pathogenic for NM_000546.5:c.1031T>G.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no ancestry-specific FAF reaches the TP53 BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no ancestry-specific FAF reaches the TP53 BS1 threshold of 0.0003.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying unaffected female carriers aged at least 60 years from a single source are reported for comparison with the TP53 BS2 thresholds.	cspec
BS3	Not met	Not met: the TP53 VCEP worksheet assigns PS3 to L344R, with Non-functional and LOF results rather than benign functional activity.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:19454241 PMID:16007150 PMID:20978130
BS4	Not assessed	Not assessed: no affected relatives with documented variant-negative testing are available to establish lack of segregation.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the governing TP53 VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: TP53 VCEP BP3 is not applicable, and p.Leu344Arg is not a repetitive-region in-frame deletion or insertion.	cspec
BP4	Not met	Not met: BayesDel 0.288212 exceeds the TP53 VCEP BP4 supporting cutoff of <0.16 despite SpliceAI max delta 0.001.	cspec vcep_pp3_bp4_codes spliceai bayesdel
BP5	N/A	Not applicable: the TP53 VCEP specification explicitly designates BP5 as Not Applicable.	cspec
BP6	Not met	Not met: the exact ClinVar expert-panel classification is Likely Pathogenic, not Benign or Likely Benign.	clinvar
BP7	N/A	Not applicable: c.1031T>G produces the missense change p.Leu344Arg, whereas BP7 is restricted to synonymous or eligible intronic variants.	cspec

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