Variant classification summary

NM_000546.6:c.375+13G>A

TP53 · NP_000537.3:p.? · NM_000546.6

GRCh37: chr17:7579299 C>T · GRCh38: chr17:7675981 C>T

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting BP4 supporting benign BP7 supporting benign

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.?

gnomAD AF

3.7218211615307603e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.6:c.375+13G>A is an intronic variant in TP53 at position +13 of intron 4, outside the canonical splice consensus sequence.

2

This variant is extremely rare in population databases, with an allele frequency of 3.72 x 10^-6 in gnomAD v4.1 (6/1,612,114 alleles), meeting TP53 VCEP PM2_Supporting.

3

SpliceAI predicts no splicing impact (max delta = 0.02), meeting TP53 VCEP BP4_Supporting and BP7_Supporting for intronic variants at or beyond +7 with SpliceAI ≤ 0.1.

4

This variant has been reported in ClinVar as Likely benign by 5 clinical laboratories (ClinVar ID 379461), though review status is 1-star (criteria provided, single submitter) and no 3-star expert panel classification exists.

5

No functional data, segregation analysis, de novo observations, or case-control studies are available for this variant. The variant does not alter a protein-coding residue and is not eligible for PVS1, PS1, PS3, PM1, PM5, or BS3 under the TP53 VCEP framework.

6

Under the TP53 VCEP v2.4 point-based system, applying PM2_Supporting (+1), BP4_Supporting (-1), and BP7_Supporting (-1) yields a total of -1 points. Per the VCEP caveat, when at least 2 benign evidence codes are applied and PM2_Supporting is the only pathogenic code, the classification may be overridden to Likely Benign.

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 -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	Intronic variant at +13 position, beyond the canonical +/-1,2 splice donor/acceptor sites. PVS1 per the TP53 VCEP v2.4 applies to nonsense, frameshift, canonical splice sites (+/-1,2), initiation codon, and exon-level deletions. This variant does not fall within any PVS1-eligible variant bucket.	pvs1_generic_framework vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	N/A	PS1 applies to nucleotide changes at the same position predicted to cause the same amino acid change as a known pathogenic missense variant. This is an intronic variant with no amino acid change (NP_000537.3:p.?); no same-residue missense comparator is possible.
PS2	Not met	No de novo observation has been reported for this variant. No proband data with confirmed maternity and paternity is available in ClinVar, the literature, or any case-level evidence source.	clinvar
PS3	N/A	The TP53 VCEP v2.4 functional assay framework (Kato, Funk, Giacomelli, Kotler, Kawaguchi) applies only to missense variants and small in-frame deletions. This intronic variant at +13 has no amino acid change and is not eligible for the VCEP functional assessment. No other functional data specific to this non-coding variant exists.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not met	No case-control data or proband counting is available for this variant. No Li-Fraumeni syndrome-affected probands with this variant have been reported. The TP53 VCEP PS4 point system requires documented probands with LFS-associated cancers; none are available.	clinvar
PS5	Not assessed	PS5 is not in the active ACMG/AMP 2015 criteria set for this adjudication.
PM3	N/A	Recessive disorder criterion — not applicable to autosomal dominant TP53-associated Li-Fraumeni syndrome.
PM4	N/A	Protein length change due to in-frame deletion/insertion — not applicable to a substitution variant.
PM1	N/A	The TP53 VCEP v2.4 PM1 applies to missense variants at specific hotspot codons (175, 245, 248, 249, 273, 282 on NM_000546.4) or cancerhotspots.org entries with ≥2 somatic occurrences. This is an intronic variant at +13, not a missense change at any of the designated codons, and is not listed at cancerhotspots.org.	cspec
PM2	Met	This variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 3.72 x 10^-6 (6/1,612,114 alleles), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. In the European (non-Finnish) subpopulation, frequency is 5.08 x 10^-6 (6/1,179,994 alleles), below the 0.004% threshold for subpopulations with multiple alleles.	gnomad_v4 cspec
PM5	N/A	PM5 requires a missense variant at the same amino acid residue as a known pathogenic missense variant. This intronic variant has no amino acid change (NP_000537.3:p.?) and is not eligible for same-residue missense PM5 assessment.	pm5_candidates
PM6	N/A	The TP53 VCEP v2.4 designates PM6 as Not Applicable. Additionally, no de novo observation with confirmed maternity and paternity is reported for this variant.	cspec
PP1	Not met	No cosegregation data is available for this variant. The TP53 VCEP PP1 requires observation in 3-4 meioses for supporting, 5-6 for moderate, and ≥7 for strong. No family studies or cosegregation analysis has been reported.
PP2	N/A	The TP53 VCEP v2.4 designates PP2 as Not Applicable. PP2 (missense variant in a gene with low rate of benign missense variation) is not used under this VCEP framework.	cspec
PP3	Not met	SpliceAI predicts no significant splicing impact (max delta score = 0.02). The TP53 VCEP PP3 threshold for intronic variants outside +/-1,2 positions is SpliceAI ≥ 0.2, which is not met. No other in silico evidence supports pathogenicity for this deep intronic variant.	spliceai cspec
PP4	Not met	The TP53 VCEP PP4 requires observation of the variant with variant allele fraction (VAF) of 5-35%, suggesting somatic mosaicism in a patient with a phenotype specific for TP53-related disease. No VAF data is available for any carrier of this variant, and no phenotype description is provided in ClinVar submissions.	clinvar cspec
PP5	N/A	The TP53 VCEP v2.4 designates PP5 as Not Applicable. ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for the global PP5 override. PP5 is not applied under this framework.	cspec clinvar
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 1.83 x 10^-6, far below the TP53 VCEP BA1 threshold of ≥0.001 (0.1%). This variant is not common enough in any population to qualify as a stand-alone benign polymorphism.	gnomad_v4 cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 1.83 x 10^-6, far below the TP53 VCEP BS1 threshold of ≥0.0003 (0.03%). The variant is too rare in population databases to meet BS1.	gnomad_v4 cspec
BS2	Not met	The TP53 VCEP BS2 requires ≥2 unrelated females aged ≥60 without cancer from a single source. No such observational data is available for this variant. No healthy elderly female carriers have been documented.
BS3	N/A	The TP53 VCEP v2.4 BS3 functional assay framework applies only to missense variants and small in-frame deletions. This intronic variant has no amino acid change and is not eligible for VCEP functional assessment.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not met	No segregation data is available to assess lack of cosegregation with LFS-associated cancers. The TP53 VCEP BS4 requires observed lack of segregation in affected family members; no family studies exist for this variant.
BP1	N/A	The TP53 VCEP v2.4 designates BP1 as Not Applicable. BP1 (missense variant in a gene where primarily truncating variants cause disease) does not apply to TP53, where both missense and truncating variants contribute to disease.	cspec
BP2	N/A	The TP53 VCEP v2.4 designates BP2 as Not Applicable. BP2 (observed in trans with a pathogenic variant) is not applicable to autosomal dominant TP53-associated Li-Fraumeni syndrome.	cspec
BP3	N/A	In-frame deletion/insertion in a repetitive region — not applicable to a substitution variant.
BP4	Met	SpliceAI predicts no splicing impact (max delta = 0.02). Per the TP53 VCEP v2.4, intronic variants outside +/-1,2 positions with SpliceAI ≤ 0.1 meet BP4_Supporting. Multiple lines of computational evidence suggest this variant does not alter splicing.	spliceai cspec vcep_pp3_bp4_codes
BP5	N/A	The TP53 VCEP v2.4 designates BP5 as Not Applicable. BP5 (variant found in a case with an alternate molecular basis for disease) is not used under this VCEP framework.	cspec
BP6	N/A	The TP53 VCEP v2.4 designates BP6 as Not Applicable. ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for the global BP6 override. BP6 is not applied under this framework.	cspec clinvar
BP7	Met	This is an intronic variant at +13 position (beyond +7 from the exon-intron boundary) with SpliceAI max delta = 0.02, predicting no impact on splicing. Per the TP53 VCEP v2.4, intronic variants at or beyond +7 with SpliceAI ≤ 0.1 meet BP7_Supporting.	spliceai cspec vcep_pp3_bp4_codes

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