Variant classification summary

NM_000546.6:c.1118A>G

TP53 · NP_000537.3:p.(Lys373Arg) · NM_000546.6

GRCh37: chr17:7572991 T>C · GRCh38: chr17:7669673 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

PM2 supporting BS3 strong BP4 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Lys373Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

TP53 c.1118A>G (p.Lys373Arg) is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting.

2

Functional evidence shows p.Lys373Arg retains p53 transactivation activity: the TP53 VCEP Functional-worksheet assigns Kato class 'Functional' with no loss of function across available eligible assays (BS3), and Kim et al. 2012 (PMID 22178617) directly observed wild-type-like (60-80%) transactivation for K373R.

3

Computational evidence supports a benign effect: BayesDel -0.107 (Class C0) and SpliceAI max delta 0.04, meeting BP4_Moderate per the TP53 VCEP.

4

ClinVar reports this variant as Uncertain significance (3 laboratories) and Likely benign (2 laboratories) with no expert-panel review, consistent with the functional and computational evidence.

Final determination: Summing the applied criteria points (+1 PM2_Supporting, -4 BS3, -2 BP4_Moderate) yields -5, which falls in the TP53 VCEP Likely Benign range (points >= -6 and <= -2), so the variant is classified Likely Benign.

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 is a missense variant (p.Lys373Arg), not a null variant (nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon deletion), so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change producing the same p.Lys373Arg substitution has been reported as pathogenic/likely pathogenic in ClinVar.	clinvar pm5_candidates
PS2	Not met	No de novo observation of this variant (with confirmed parentage) has been reported.
PS3	Not met	Functional data indicate p.Lys373Arg retains p53 transactivation activity (Kato class 'Functional' per the VCEP Functional-worksheet; Kim et al. 2012 observed 60-80% of wild-type activity), which is evidence of retained function rather than loss of function, so PS3 is not met.	vcep_functional_worksheet PMID:22178617
PS4	Not met	No proband phenotype or case-control data are available to tally Li-Fraumeni syndrome cancer points.
PS5	Not met	PS5 (same nucleotide change previously established as pathogenic) is not part of the TP53 VCEP criteria and no such evidence exists; ClinVar reports this variant as VUS/Likely benign.	clinvar
PM1	Not met	p.Lys373Arg lies in the C-terminal regulatory domain, outside the TP53 VCEP PM1 hotspot codons (175, 245, 248, 249, 273, 282); cancerhotspots.org does not flag this residue as significant (COSMIC n=1), so PM1 is not met.	cspec oncokb
PM2	Met	The variant is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting (allele frequency <0.003%).	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic/likely pathogenic missense variant at codon 373 was identified as a comparator (PM5 candidate search returned zero candidates).	pm5_candidates clinvar
PM6	N/A	PM6 (assumed de novo without confirmed parentage) is not applicable under the TP53 VCEP, which uses a combined PS2/PM6 de novo rule.
PP1	Not met	No cosegregation data are available for this variant.
PP2	N/A	PP2 (missense variant in a gene with a low rate of benign missense variation) is not applicable under the TP53 VCEP.
PP3	Not met	Computational evidence does not support a deleterious effect: BayesDel -0.107 (Class C0), REVEL 0.407, SpliceAI max delta 0.04; the TP53 VCEP PP3-BP4-codes table assigns 'BP4_moderate' rather than PP3.	vcep_pp3_bp4_codes bayesdel revel spliceai
PP4	Not met	No observation of the variant with variant allele fraction 5-35% is available to meet PP4.
PP5	N/A	PP5 is not for use under the TP53 VCEP; the ClinVar review status is 'criteria provided, single submitter' with no 3-star expert-panel pathogenic classification.	clinvar
BA1	Not met	The variant is absent from gnomAD, far below the BA1 stand-alone benign threshold (FAF >=0.1%).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD, below the BS1 strong benign threshold (FAF >=0.03%).	gnomad_v2 gnomad_v4
BS2	Not met	No data on unrelated females who reached 60 years of age without cancer are available.
BS3	Met	p.Lys373Arg is functional in the Kato assay (TP53 VCEP Functional-worksheet: 'Functional') with no loss of function by available eligible assays (Giacomelli 'noLOF'); Kim et al. 2012 directly tested K373R and observed wild-type-like transactivation (60-80% of wild type). This meets BS3 (Strong).	vcep_functional_worksheet PMID:22178617
BS4	Not met	No segregation data indicating lack of segregation in affected family members are available.
BP1	N/A	BP1 (missense variant in a gene where primarily truncating variants cause disease) is not applicable under the TP53 VCEP.
BP2	N/A	BP2 (observation in trans/cis with a pathogenic variant) is not applicable under the TP53 VCEP, and no such data are available.
BP4	Met	BP4_Moderate: BayesDel -0.107 (<= -0.008, Class C0) with no predicted splicing impact (SpliceAI max delta 0.04) meets the TP53 VCEP BP4_moderate rule.	vcep_pp3_bp4_codes bayesdel spliceai
BP5	N/A	BP5 (variant found in a case with an alternate molecular basis for disease) is not applicable under the TP53 VCEP.
BP6	N/A	BP6 is not for use under the TP53 VCEP, and there is no 3-star expert-panel benign classification in ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants; this is a missense variant (p.Lys373Arg).
BP3	N/A	In-frame deletion/insertion in a repetitive region; this is a missense substitution.
PM3	N/A	Recessive-disorder criterion; TP53/Li-Fraumeni syndrome is autosomal dominant.
PM4	N/A	Protein-length change (in-frame indel/stop-loss); this is a missense substitution.

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