Variant classification summary

NM_000546.6:c.390C>T

TP53 · NP_000537.3:p.(Leu130=) · NM_000546.6

GRCh37: chr17:7578540 G>A · GRCh38: chr17:7675222 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Benign

BP4 supporting benign BP7 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Leu130=)

gnomAD AF

7.435349634924333e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.6:c.390C>T (p.Leu130=) is a synonymous variant in exon 5 of TP53. SpliceAI predicts no splicing impact (max delta score 0.01). The variant is present at very low frequency in gnomAD (v2.1: 6/250,352 alleles; v4.1: 12/1,613,912 alleles) though the Admixed American subpopulation carries multiple alleles with AF above the PM2 subpopulation ceiling. BP7_Supporting is met as a synonymous variant outside the core splice motif with no predicted splicing effect.

2

No pathogenic criteria are met. PVS1, PS1, and PM5 are not applicable (synonymous variant). PM1 is not met (not a missense at a VCEP-designated hotspot codon). PM2 is not met (AMR subpopulation AF exceeds 0.004% ceiling). PS3 and BS3 are not met (VCEP functional rules apply only to missense and in-frame deletions). No proband-level clinical data were available to assess PS2, PS4, PP1, PP4, BS2, or BS4.

3

The only met criterion is BP7_Supporting (-1 point under the Tavtigian Bayesian point system). This places the variant in the VUS range (total points = -1). No pathogenic evidence criteria are met to elevate classification.

Final determination: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework yields a total score of -2, which maps to Likely Benign 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 applies only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). NM_000546.6:c.390C>T is a synonymous variant (NP_000537.3:p.Leu130=) and does not fall into any PVS1-eligible variant class per the TP53 VCEP PVS1 flowchart.
PS1	N/A	PS1 applies when the variant produces the same amino acid change as a previously established pathogenic variant. NM_000546.6:c.390C>T is synonymous (p.Leu130=) and produces no amino acid change, so there is no comparator amino acid change to evaluate.
PS2	Not assessed	No de novo observation data were provided for this case. PS2 requires proband-level data with cancer history and confirmed parentage for scoring under the TP53 VCEP LFS points system.
PS3	Not met	The TP53 VCEP functional assay rules (PS3/BS3 flowchart and Functional-worksheet.xlsx) apply only to missense amino acid substitutions and small in-frame deletions. NM_000546.6:c.390C>T is a synonymous variant with no predicted amino acid change; the VCEP functional framework does not provide for assessment of synonymous variants. No variant-specific functional data were identified in the literature.	cspec
PS4	Not assessed	No proband-level case data with LFS cancer diagnoses were provided. PS4 under the TP53 VCEP requires proband counts scored against the LFS cancer points table (PS4-Points-Table.pdf) to determine strength.
PS5	Not assessed	PS5 is not part of the standard ACMG/AMP criteria set for this assessment task.
PM1	Not met	The TP53 VCEP restricts PM1 to missense variants at specified hotspot codons (175, 245, 248, 249, 273, 282) or germline missense variants with sufficient somatic occurrences at cancerhotspots.org. NM_000546.6:c.390C>T is a synonymous variant at codon 130, which is not among the VCEP-defined PM1 hotspot codons and is not a missense variant.	cspec
PM2	Not met	Total gnomAD allele frequencies are below the VCEP PM2_Supporting threshold of 0.003% (v2.1: AF=0.00240%, 6/250352; v4.1: AF=0.00074%, 12/1613912). However, the Admixed American (AMR) subpopulation carries multiple alleles with an AF exceeding the 0.004% subpopulation ceiling in both gnomAD versions (v2.1: 2/34564, AF=0.00579%; v4.1: 5/59998, AF=0.00833%). Under the TP53 VCEP rule, when multiple alleles are present in any non-founder genetic ancestry group, that group's AF must remain below 0.004%. This criterion is not met.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	PM5 applies to missense variants at an amino acid residue where a different pathogenic/likely pathogenic missense change has been reported. NM_000546.6:c.390C>T is a synonymous variant (p.Leu130=); PM5 is not applicable to synonymous variants.
PM6	N/A	The TP53 VCEP merges PM6 with PS2 into a single combined de novo rule; PM6 is listed as Not Applicable in the VCEP specification.	cspec
PP1	Not assessed	No cosegregation data were provided. PP1 under the TP53 VCEP requires meiotic counts across families (3-4 meioses for supporting, 5-6 for moderate, ≥7 for strong).
PP2	N/A	The TP53 VCEP lists PP2 as Not Applicable.	cspec
PP3	Not met	The TP53 VCEP PP3 rules for missense variants require aGVGD class C25-C65 or C65 with BayesDel ≥0.16; for exonic variants with predicted splicing effect, SpliceAI ≥0.2 is required. NM_000546.6:c.390C>T is a synonymous variant with SpliceAI max delta of 0.01, well below the 0.2 threshold. No evidence supports a pathogenic computational prediction for this variant. The variant is absent from the VCEP PP3-BP4-codes.xlsx pre-computed assignments.	spliceai cspec
PP4	Not assessed	No variant allele fraction (VAF) data were provided. PP4 under the TP53 VCEP requires VAF observations in the 5-35% range to assess clonal hematopoiesis/mosaicism patterns.
PP5	N/A	The TP53 VCEP explicitly marks PP5 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	The TP53 VCEP BA1 threshold is a filtering allele frequency (FAF) ≥0.001 (0.1%) in a non-founder gnomAD continental subpopulation. The grpmax FAF for this variant is 3.233e-05 (v4.1) and 9.58e-06 (v2.1), both far below the 0.001 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The TP53 VCEP BS1 threshold is a filtering allele frequency (FAF) ≥0.0003 but <0.001 in a non-founder gnomAD continental subpopulation with ≥2000 alleles and ≥2 alleles present. The grpmax FAF is 3.233e-05 (v4.1), below the 0.0003 minimum threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No data on unrelated females aged ≥60 years without cancer were provided. BS2 under the TP53 VCEP requires counts of unaffected elderly females from a single source.
BS3	Not met	The TP53 VCEP functional assay rules (BS3 flowchart and Functional-worksheet.xlsx) apply only to missense amino acid substitutions and small in-frame deletions. NM_000546.6:c.390C>T is a synonymous variant with no predicted amino acid change; the VCEP functional framework does not provide for assessment of synonymous variants. No functional evidence demonstrating normal protein function was identified for this specific variant.	cspec
BS4	Not assessed	No segregation data in affected family members were provided. BS4 under the TP53 VCEP requires demonstration of lack of segregation in family members with LFS-associated cancers.
BP1	N/A	The TP53 VCEP lists BP1 as Not Applicable; truncating variants account for only a portion of disease-causing variants in TP53.	cspec
BP2	N/A	The TP53 VCEP lists BP2 as Not Applicable.	cspec
BP4	Met	NM_000546.6:c.390C>T is a silent/synonymous variant outside the canonical splice sites (±1,2 positions). SpliceAI predicts no splicing impact (max delta score = 0.01, ≤0.1 threshold for silent variants). Per the TP53 VCEP BP4 rules for silent/intronic variants: SpliceAI ≤0.1 satisfies BP4_Supporting. Note: BP7 is the more specific code for synonymous variants and is assessed separately; BP4 is reported here per the VCEP specification which lists BP4 as a prerequisite for BP7_Supporting.	spliceai cspec
BP5	N/A	The TP53 VCEP lists BP5 as Not Applicable.	cspec
BP6	N/A	The TP53 VCEP explicitly marks BP6 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	Met	NM_000546.6:c.390C>T is a synonymous variant at position c.390 within exon 5 (c.376-c.559). The variant is outside the core splice motif (last three nucleotides and first nucleotide of the exon). SpliceAI predicts no impact to the splice consensus and no creation of a new splice site (max delta score = 0.01 ≤ 0.1, BP4 criterion met). Per the TP53 VCEP BP7_Supporting rule for synonymous variants outside the core splice motif with SpliceAI ≤0.1, this criterion is met at supporting benign strength.	spliceai cspec

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