Variant classification summary

NM_000546.5:c.214C>T

TP53 · NP_000537.3:p.(Pro72Ser) · NM_000546.5

GRCh37: chr17:7579473 G>A · GRCh38: chr17:7676155 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting BP4 moderate

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Pro72Ser)

gnomAD AF

6.816767761398255e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.5:c.214C>T (p.Pro72Ser) is a missense variant in exon 4 of TP53 at codon 72, a known common polymorphic site (rs1042522).

2

The variant is present at very low frequency in gnomAD v2.1 (4/250,672 alleles; AF=0.00160%) and v4.1 (11/1,613,668 alleles; AF=0.00068%), meeting the TP53 VCEP PM2_Supporting threshold of <0.003% total allele frequency with subpopulation AF <0.004%.

3

The variant is assigned BP4_moderate by the TP53 VCEP bioinformatic codes (Supplementary Table S2), with a BayesDel score of -0.202922 and no predicted splicing impact (SpliceAI max delta = 0.00).

4

The variant has been reported in ClinVar as Likely benign (Ambry Genetics, 1 submission) and Uncertain significance (Labcorp/Invitae, 1 submission). No expert panel review is available. (ClinVar VariationID: 485023)

5

The variant has been observed in somatic cancers (COSMIC, COSV52665238, n=6), but lies outside the TP53 VCEP-defined mutational hotspots (codons 175, 245, 248, 249, 273, 282).

6

No functional data from VCEP-eligible assays are available for p.Pro72Ser; the variant is absent from the VCEP Functional-worksheet (Supplementary Table S3).

7

Under the Tavtigian point-based system (TP53 VCEP v2.4.0), the evidence tally is PM2_Supporting (+1) + BP4_Moderate (-2) = -1 point, consistent with a classification of Uncertain Significance.

8

The VCEP CAVEAT allowing reclassification of -1 points to Likely Benign (requiring ≥2 benign codes and PM2_Supporting as the only pathogenic code) is not met, as only one benign code (BP4_Moderate) is applied.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -1, 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	NM_000546.5:c.214C>T is a missense variant (p.Pro72Ser), not a null variant. PVS1 under the TP53 VCEP is applicable only to nonsense, frameshift, canonical splice site, initiation codon, and CNV variants as defined in the PVS1 flowchart.
PS1	N/A	p.Pro72Ser is produced by c.214C>T (CCC→TCC). No alternative single-nucleotide change at codon 72 produces the same amino acid change (Ser). PS1 requires the same amino acid change from a different nucleotide change, which is not possible for this variant.
PS2	Not met	No de novo observation data are available for this variant. No proband-specific information with confirmed parentage or LFS-associated cancer phenotype was provided in the case materials.
PS3	Not assessed	The TP53 VCEP Functional-worksheet (Supplementary Table S3) does not contain an entry for the p.Pro72Ser (P72S) amino acid substitution. Codon 72 is a known common polymorphic site (rs1042522, Pro72Arg). No functional data from VCEP-eligible assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi) are available for this specific variant.
PS4	Not assessed	No proband-level phenotype data or LFS cancer point tallies are available in the case materials. PS4 under the TP53 VCEP requires proband-specific cancer diagnoses scored against the Li-Fraumeni syndrome points table (strongly associated cancers = 4 points, moderately associated = 2 points).
PS5	N/A	Skipped per adjudication instructions.
PM1	Not met	Codon 72 is not among the TP53 VCEP-defined mutational hotspots (codons 175, 245, 248, 249, 273, 282). The variant is not listed at cancerhotspots.org as a significant residue, and the exact variant is not listed as a recurrent hotspot.
PM2	Met	The variant is present at very low frequency in population databases. In gnomAD v2.1, the total allele frequency is 0.00160% (4/250,672 alleles), below the VCEP PM2_Supporting threshold of 0.003%. The highest subpopulation frequency (European non-Finnish) is 0.00353% (4/113,442 alleles), below the VCEP subpopulation cutoff of 0.004%. In gnomAD v4.1, the total allele frequency is 0.00068% (11/1,613,668 alleles). The variant is absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	Codon 72 is a known common polymorphic site (rs1042522, Pro72Arg). No other missense variants at this codon have been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. The PM5 candidate search identified zero eligible comparator variants at this residue.	pm5_candidates
PM6	N/A	PM6 is not applicable under the TP53 VCEP specifications (version 2.4.0).
PP1	Not met	No cosegregation data are available for this variant. PP1 under TP53 VCEP requires specific meioses counts (3-4 meioses for Supporting, 5-6 for Moderate, ≥7 for Strong) in families with LFS-associated cancers.
PP2	N/A	PP2 is not applicable under the TP53 VCEP specifications.
PP3	Not met	The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns BP4_moderate to c.214C>T, not PP3. The BayesDel score is -0.202922 (Class C0), which does not meet the PP3 thresholds (BayesDel ≥ 0.16 required for PP3_Supporting or PP3_Moderate). REVEL score is 0.314, but the VCEP uses BayesDel and aGVGD, not REVEL, for PP3/BP4 adjudication.	vcep_pp3_bp4_codes bayesdel
PP4	Not met	PP4 under the TP53 VCEP is based on variant allele fraction (VAF) observations in blood specimens (5-25% for Moderate, 5-35% for Supporting), reflecting concern for clonal hematopoiesis/somatic mosaicism. No VAF data are provided for this variant to meet PP4 thresholds.
PP5	N/A	PP5 is not recommended for use by the ClinGen Sequence Variant Interpretation VCEP Review Committee for TP53.
BA1	Not met	The highest filtering allele frequency (FAF) observed in any gnomAD continental subpopulation is 1.12e-05 (gnomAD v2.1, European non-Finnish). This is far below the VCEP BA1 threshold of ≥ 0.001 (0.1%).	gnomad_v2 gnomad_v4
BS1	Not met	The highest filtering allele frequency in any gnomAD continental subpopulation is 1.12e-05 (v2.1 grpmax FAF), which falls below the VCEP BS1 threshold of ≥ 0.0003 (0.03%). The subpopulation with the highest frequency, European non-Finnish (AF=0.00353%, 4/113,442), also remains below this threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in unrelated females who have reached at least 60 years of age without cancer, as required for BS2 under the TP53 VCEP.
BS3	Not assessed	The TP53 VCEP Functional-worksheet (Supplementary Table S3) does not contain an entry for the p.Pro72Ser (P72S) amino acid substitution. No functional data from VCEP-eligible assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi) are available for this variant. BS3 cannot be applied without assay data.
BS4	Not met	No segregation data are available to assess lack of segregation with LFS-associated cancers in affected family members, as required for BS4 under the TP53 VCEP.
BP1	N/A	BP1 is not applicable under the TP53 VCEP; truncating variants account for only a portion of disease-causing variants in TP53.
BP2	N/A	BP2 is not applicable under the TP53 VCEP specifications for this variant.
BP4	Met	The TP53 VCEP PP3-BP4-codes spreadsheet (Supplementary Table S2) directly assigns BP4_moderate to c.214C>T (p.Pro72Ser). The variant has a BayesDel score of -0.202922 (Class C0), which is ≤ -0.008, meeting the VCEP BP4_Moderate threshold. aGVGD class is C0 (not C65, so no exclusion applies). SpliceAI predicts no splicing impact (max delta = 0.00, which is < 0.2), satisfying the requirement of no predicted splicing differences.	vcep_pp3_bp4_codes bayesdel spliceai
BP5	N/A	BP5 is not applicable under the TP53 VCEP specifications.
BP6	N/A	BP6 is not recommended for use by the ClinGen Sequence Variant Interpretation VCEP Review Committee for TP53.
BP7	N/A	c.214C>T is a missense variant (p.Pro72Ser), not a synonymous (silent) or intronic variant. BP7 under the TP53 VCEP applies only to synonymous variants or intronic variants outside ±1,2 positions.

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