Variant classification summary

NM_000546.6:c.293C>G

TP53 · NP_000537.3:p.(Pro98Arg) · NM_000546.6

GRCh37: chr17:7579394 G>C · GRCh38: chr17:7676076 G>C

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.(Pro98Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2_Supporting is met: NM_000546.6:c.293C>G (p.Pro98Arg) is absent from gnomAD v2.1 and v4.1 (0 alleles across all populations), satisfying the VCEP PM2_Supporting threshold of allele frequency <0.00003.

2

PP3_Moderate is met: The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G. This variant has aGVGD Class C65 and BayesDel score 0.591769 (≥0.16), with no predicted splicing impact (SpliceAI max delta 0.00). REVEL score of 0.955 provides additional in silico support.

3

PVS1 is not applicable: this is a missense variant; the TP53 VCEP reserves PVS1 for null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletions).

4

PS3 and BS3 are not met: the VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg. Kato class is 'Partially functional' and Giacomelli reports 'noLOF', which does not satisfy VCEP PS3 or BS3 criteria thresholds.

5

PM1 is not met: codon 98 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282), and the residue is not a statistically significant hotspot on cancerhotspots.org. PM5 is not met: no other Pro98 missense variant has a VCEP P/LP classification.

6

PS1, PS2, PS4, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4 are not met based on absence of qualifying evidence from ClinVar, gnomAD, published literature, and VCEP reference data.

7

PP5, BP1, BP2, BP5, BP6, PM6, PP2, and BP3 are not applicable under the TP53 VCEP v2.4.0 specifications. PS5 is not included in the VCEP criteria set. BP7 is not applicable as this is a missense variant.

8

Tavtigian point tally: PM2_Supporting (+1) + PP3_Moderate (+2) = 3 points. Per TP53 VCEP v2.4.0 ranges: ≥10 Pathogenic, 6-9 Likely Pathogenic, -1 to 5 Uncertain Significance, -6 to -2 Likely Benign, ≤-7 Benign. Total of 3 points classifies this variant as Uncertain Significance (VUS).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 3, which maps to VUS under the specified Tavtigian-style ranges.

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	PVS1 is not applicable. This variant is a missense substitution (p.Pro98Arg), and the TP53 VCEP reserves PVS1 for null variants only: nonsense, frameshift, canonical splice ±1/2, initiation codon, and exon-level deletions.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	PS1 is not met. No other missense variant at codon Pro98 has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. The VCEP Functional worksheet assigns 'No evidence' to all tested Pro98 variants (P98A, P98H, P98L, P98S, P98T), and no Pro98 variant has a VCEP-established pathogenic classification.	vcep_functional_worksheet cspec
PS2	Not met	PS2 is not met. No de novo occurrence with confirmed maternity and paternity has been identified for this variant in ClinVar submissions, the published literature, or the IARC TP53 database.	clinvar cspec
PS3	Not met	PS3 is not met. The VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg. Kato et al. (PMID:12826609) classifies this variant as 'Partially functional', and Giacomelli et al. (PMID:30224644) reports 'noLOF'. Under VCEP rules, PS3_Moderate requires LOF by majority of other available assays (not met; only Giacomelli has data and shows noLOF), and PS3_Supporting requires Kato to be non-functional (not met; Kato shows partially functional). No other eligible functional assays (Funk, Kotler, Kawaguchi) have data for this residue.	vcep_functional_worksheet cspec PMID:12826609 PMID:30224644
PS4	Not met	PS4 is not met. No probands with specific Li-Fraumeni syndrome cancer diagnoses have been identified to allow case-count scoring under the VCEP PS4 point table (PS4-Points-Table.pdf). No case-control study has reported this variant in an affected cohort. ClinVar submissions do not provide quantifiable case counts with phenotype data.	clinvar cspec vcep_ps4_points_table
PS5	N/A	PS5 is not applicable. The TP53 VCEP v2.4.0 does not include PS5 in its criteria set; this criterion is not recognized by the expert panel specifications.	cspec
PM1	Not met	PM1 is not met. Codon 98 is not among the VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282). The residue is not listed as a statistically significant hotspot on cancerhotspots.org, and the COSMIC count of 3 somatic occurrences does not independently meet the VCEP PM1_Supporting threshold as the variant is not recognized in cancerhotspots.org.	cspec
PM2	Met	PM2_Supporting is met. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0 in all populations. This satisfies the VCEP PM2_Supporting threshold of an allele frequency less than 0.00003 (0.003%).	gnomad_v2 gnomad_v4 cspec
PM5	Not met	PM5 is not met. No other missense variant at codon Pro98 has been classified as Pathogenic or Likely Pathogenic by the TP53 VCEP. The VCEP Functional worksheet assigns 'No evidence' to all tested Pro98 alternative substitutions (P98A, P98H, P98L, P98S, P98T), and ClinVar contains no VCEP-level P/LP classifications for any Pro98 variant.	vcep_functional_worksheet cspec pm5_candidates
PM6	N/A	PM6 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PM6 as Not Applicable.	cspec
PP1	Not met	PP1 is not met. No cosegregation data have been identified for this variant in families with Li-Fraumeni syndrome or TP53-associated cancers. No published family studies or ClinVar submission annotations describe meiotic segregation data.	clinvar cspec
PP2	N/A	PP2 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PP2 as Not Applicable.	cspec
PP3	Met	PP3_Moderate is met. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.293C>G (p.Pro98Arg). This variant has aGVGD Class C65 and a BayesDel score of 0.591769 (≥0.16), satisfying the VCEP PP3_moderate rule. SpliceAI max delta score is 0.00 (<0.2), confirming no predicted splicing impact that would alter the code assignment. REVEL score of 0.955 provides additional in silico support.	vcep_pp3_bp4_codes cspec revel bayesdel spliceai
PP4	Not met	PP4 is not met. No observations of this variant with documented variant allele fraction (VAF) data have been identified. The VCEP PP4 rule requires at least one observation with VAF 5-35% (supporting) or at least two independent observations with VAF 5-25% (moderate). No VAF data are available in ClinVar submissions or the literature.	clinvar cspec
PP5	N/A	PP5 is not applicable. The TP53 VCEP v2.4.0 explicitly lists PP5 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	BA1 is not met. The variant is absent from gnomAD v2.1 and v4.1. The VCEP BA1 threshold requires a filtering allele frequency ≥0.001 in a single continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. Absence from population databases precludes application of BA1.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	BS1 is not met. The variant is absent from gnomAD. The VCEP BS1 threshold requires a filtering allele frequency ≥0.0003 but <0.001 in a single continental subpopulation. Zero alleles across all populations does not satisfy this criterion.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	BS2 is not met. No data have been identified describing unrelated healthy females aged ≥60 years without cancer who carry this variant. The VCEP BS2 rule requires at least 2 such individuals from a single source. No such observations exist in ClinVar or the literature.	clinvar cspec
BS3	Not met	BS3 is not met. The VCEP Functional-worksheet.xlsx assigns 'No evidence' for p.Pro98Arg, which is the authoritative pre-assigned code. Although Kato et al. classifies this variant as 'Partially functional' and Giacomelli et al. reports 'noLOF' (which could nominally approach BS3_Supporting under VCEP rules), the VCEP expert panel's consolidated code 'No evidence' takes precedence and does not apply a benign functional code.	vcep_functional_worksheet cspec PMID:12826609 PMID:30224644
BS4	Not met	BS4 is not met. No family data have been identified showing lack of segregation of this variant with Li-Fraumeni syndrome-associated cancers. No reports describe an unaffected family member carrying the variant in a family with a clear TP53-related phenotype.	clinvar cspec
BP1	N/A	BP1 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP1 as Not Applicable.	cspec
BP2	N/A	BP2 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP2 as Not Applicable.	cspec
BP3	N/A	BP3 is not applicable. In-frame deletions/insertions in a repetitive region without known function. This is a missense substitution, not an in-frame indel.
BP4	Not met	BP4 is not met. Under VCEP rules, BP4 is expressly excluded for aGVGD Class C65 variants: 'BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4).' Since this variant is classified as aGVGD Class C65, BP4 cannot be applied regardless of the BayesDel score.	vcep_pp3_bp4_codes cspec bayesdel spliceai
BP5	N/A	BP5 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP5 as Not Applicable.	cspec
BP6	N/A	BP6 is not applicable. The TP53 VCEP v2.4.0 explicitly lists BP6 as Not Applicable.	cspec
BP7	N/A	BP7 is not applicable. This is a missense variant (p.Pro98Arg), not a synonymous/silent or intronic variant. The VCEP BP7 criterion applies only to synonymous (silent) variants outside the core splice motif or intronic variants at or beyond +7 to -21 positions.	cspec

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