Variant classification summary

NM_000546.5:c.413C>A

TP53 · NP_000537.3:p.(Ala138Asp) · NM_000546.5

GRCh37: chr17:7578517 G>T · GRCh38: chr17:7675199 G>T

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Ala138Asp)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.413C>A (p.Ala138Asp) in TP53 is a missense variant in exon 5. It is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

2

In silico predictions are consistent with a deleterious effect: aGVGD Class C65, BayesDel 0.540498, REVEL 0.901, and SpliceAI predicts no splicing impact (max delta 0.01). The TP53 VCEP assigns PP3_moderate.

3

Functional data from the TP53 VCEP Functional-worksheet (Supplementary Table S3) assign 'No evidence' to p.Ala138Asp: Kato shows partially functional, Funk shows LOF, but Giacomelli and Kotler show noLOF. Neither PS3 nor BS3 criteria are met.

4

The variant is not located in a VCEP-specified PM1 hotspot codon (175, 245, 248, 249, 273, 282), and the exact variant is not listed in cancerhotspots.org (PM1 not met).

5

This variant has been reported in ClinVar as Uncertain Significance by the ClinGen TP53 Variant Curation Expert Panel (ClinVar ID: 528270) and has been observed 3 times in somatic cancers (COSMIC COSV53502932).

6

PVS1, PS5, PM6, PP2, PP5, BP1, BP2, BP5, BP6, and BP7 are not applicable per the TP53 VCEP v2.4.0 specifications or by variant type. PS1, PS2, PS4, PM5, PP1, PP4, BS2, BS4, and BS5 remain not assessed due to insufficient clinical data.

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	This variant is a missense substitution (p.Ala138Asp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice sites, initiation codon, or gene deletions) and does not apply to missense variants.
PS1	Not assessed	No evidence of a different nucleotide change resulting in the same amino acid substitution (p.Ala138Asp) that has been classified as pathogenic or likely pathogenic per TP53 VCEP specifications.
PS2	Not assessed	No de novo observations have been reported for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed.
PS3	Not met	The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp. Kato assay shows partially functional (not non-functional), and the majority of available assays do not show loss of function: Funk=LOF, Giacomelli=noLOF, Kotler=noLOF (1/3 LOF is not a majority). PS3 requires non-functional on Kato, and PS3_Moderate requires LOF by the majority of assays; neither condition is met.	vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
PS4	Not assessed	No proband-level data with LFS cancer phenotypes are available for point scoring under the TP53 VCEP PS4 point system. PS4 requires counting probands with strongly or moderately associated LFS cancers per the PS4-Points-Table.
PS5	N/A	PS5 applies to recessive disorders where a different pathogenic variant is observed in trans. TP53-associated Li-Fraumeni syndrome is autosomal dominant; PS5 is not applicable.
PM1	Not met	Codon 138 is not among the TP53 VCEP-specified PM1 hotspot codons (175, 245, 248, 249, 273, 282). The exact variant p.Ala138Asp is not listed in cancerhotspots.org, precluding the alternate cancerhotspots-based PM1 route which requires ≥10 somatic occurrences for the same amino acid change.
PM2	Met	The variant is absent from gnomAD v2.1 and v4.1 (allele count = 0), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.003% (0.00003) in large population databases.	gnomad_v2 gnomad_v4
PM5	Not assessed	The pm5_candidates search found no same-residue comparator variants with definitive VCEP pathogenic/likely pathogenic classification. While A138P has PS3 and A138V has PS3_Moderate in the Functional-worksheet, the full VCEP classification (pathogenic vs. likely pathogenic) for these comparator variants is not established in the available evidence.	vcep_functional_worksheet
PM6	N/A	The ClinGen TP53 VCEP specifications designate PM6 as 'Not Applicable' for this gene.	cspec
PP1	Not assessed	No cosegregation data are available for this variant. PP1 requires observation of cosegregation in 3-4 meioses (Supporting), 5-6 meioses (Moderate), or ≥7 meioses across >1 family (Strong).
PP2	N/A	The ClinGen TP53 VCEP specifications designate PP2 as 'Not Applicable' for this gene.	cspec
PP3	Met	The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) assigns PP3_moderate to c.413C>A (p.Ala138Asp) based on aGVGD Class C65 and BayesDel score 0.540498. SpliceAI max delta is 0.01, indicating no predicted splicing impact, which does not alter the missense-based bioinformatic code. REVEL score is 0.901, consistent with a deleterious prediction.	vcep_pp3_bp4_codes spliceai revel bayesdel
PP4	Not assessed	No proband-level variant allele fraction (VAF) data are available. PP4 requires observation of the variant with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate).
PP5	N/A	The ClinGen TP53 VCEP specifications designate PP5 as 'Not Applicable for this VCEP' per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0). The TP53 VCEP BA1 threshold requires a filtering allele frequency ≥0.001 (0.1%) in a continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (FAF = 0). The TP53 VCEP BS1 threshold requires a filtering allele frequency ≥0.0003 in a continental subpopulation.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on unrelated females who have reached ≥60 years of age without cancer are available. BS2 requires ≥2 such individuals from a single source (Supporting), 4-7 (Moderate), or ≥8 (Strong).
BS3	Not met	The TP53 VCEP Functional-worksheet (Supplementary Table S3) assigns 'No evidence' to p.Ala138Asp. BS3 requires functional on Kato data AND no LOF by the majority of available assays; Kato shows partially functional (not functional). BS3_Supporting requires partially functional on Kato AND no LOF by all available assays, but Funk shows LOF, so this is not met.	vcep_functional_worksheet PMID:12826609 PMID:29979965 PMID:30224644
BS4	Not assessed	No segregation data are available to assess lack of segregation in affected family members. BS4 requires absence of segregation with LFS-associated cancers.
BP1	N/A	The ClinGen TP53 VCEP specifications designate BP1 as 'Not Applicable' for this gene.	cspec
BP2	N/A	The ClinGen TP53 VCEP specifications designate BP2 as 'Not Applicable' for this gene.	cspec
BP4	Not met	BayesDel score is 0.540498, which is well above the BP4 thresholds (BP4_Moderate requires ≤ -0.008; BP4_Supporting requires < 0.16). SpliceAI max delta is 0.01 (no predicted splicing impact), but the BayesDel score is not in the benign range.	bayesdel spliceai vcep_pp3_bp4_codes
BP5	Not assessed	No evidence of an alternative molecular basis for disease has been identified. BP5 is designated as 'Not Applicable' by the TP53 VCEP v2.4.0.	cspec
BP6	N/A	The ClinGen TP53 VCEP specifications designate BP6 as 'Not Applicable' for this gene.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants. This is a missense variant (c.413C>A, p.Ala138Asp) and BP7 does not apply.

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