Variant classification summary

NM_000546.6:c.-29+102T>G

TP53 · NP_000537.3:p.? · NM_000546.6

GRCh37: chr17:7590593 A>C · GRCh38: chr17:7687275 A>C

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.6:c.-29+102T>G is an intronic variant in TP53 located at position +102 in intron 1.

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2_Supporting per TP53 VCEP specifications (allele frequency <0.00003).

3

SpliceAI predicts no impact on splicing (max delta score 0.00), meeting BP4_Supporting and BP7_Supporting per TP53 VCEP specifications (SpliceAI ≤0.1 for intronic variants).

4

VCEP Tavtigian point tally: PM2_Supporting (+1), BP4_Supporting (−1), BP7_Supporting (−1) = −1, which falls in the VUS range (−1 to 5).

5

Per the VCEP CAVEAT, a final point value of −1 is overridden to Likely Benign when at least two benign evidence codes are applied and PM2_Supporting is the only pathogenic code applied. With BP4_Supporting and BP7_Supporting as the two benign codes, this override applies.

6

No publications identified for this variant; absent from ClinVar and COSMIC.

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_000546.6:c.-29+102T>G is an intronic variant located at +102 in intron 1, outside the canonical ±1,2 splice consensus. It does not fall into any of the TP53 VCEP PVS1 null-variant buckets (nonsense, frameshift, canonical splice site, initiation codon, exon deletion, CNV).	pvs1_variant_assessment vcep_pvs1_flowchart
PS1	N/A	PS1 requires a missense variant with the same amino acid change as an established pathogenic variant. This is an intronic variant with no amino acid consequence.
PS2	Not assessed	No de novo data or proband information is available for this variant. The VCEP PS2 point system requires proband cancer phenotype data, which has not been provided.
PS3	N/A	VCEP PS3/BS3 functional rules apply to missense variants and small in-frame deletions only. This intronic variant is not covered by the functional assay framework and was not found in the VCEP Functional-worksheet.xlsx.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
PS4	Not assessed	No proband prevalence data is available. The variant is absent from ClinVar, and no LFS-associated cancer phenotype data has been provided to apply the VCEP PS4 point system.	clinvar
PS5	N/A	PS5 is not a criterion in the TP53 VCEP v2.4.0 specifications and is not included in the standard ACMG/AMP 2015 framework.
PM1	N/A	VCEP PM1 applies to missense variants within hotspot codons (175, 245, 248, 249, 273, 282) or with ≥2 somatic occurrences at cancerhotspots.org for the same amino acid change. This is an intronic variant with no amino acid change.	cspec
PM2	Met	NM_000546.6:c.-29+102T>G is absent from both gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a missense variant at an amino acid residue where a different pathogenic missense change has been established. This is an intronic variant with no amino acid consequence.	pm5_candidates
PM6	N/A	PM6 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications.	cspec
PP1	Not assessed	No cosegregation data is available for this variant. The VCEP PP1 point system requires meiotic segregation data across families, which has not been provided.
PP2	N/A	PP2 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications.	cspec
PP3	Not met	VCEP PP3 for intronic variants requires SpliceAI ≥0.2. This variant has a SpliceAI max delta score of 0.00, indicating no predicted splicing impact.	spliceai cspec
PP4	Not assessed	The VCEP PP4 rule requires VAF data (5-35%) from patient observations. No VAF or patient phenotype information has been provided for this variant.
PP5	N/A	PP5 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	VCEP BA1 requires a filtering allele frequency ≥0.001 (0.1%) in a gnomAD continental subpopulation. This variant is absent from gnomAD and does not meet the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	VCEP BS1 requires a filtering allele frequency ≥0.0003 (0.03%) but <0.001 in a gnomAD continental subpopulation. This variant is absent from gnomAD and does not meet the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	VCEP BS2 requires observations in older unaffected females (≥60 years without cancer). No such data is available for this variant.
BS3	N/A	VCEP BS3 functional rules apply to missense variants and small in-frame deletions only. This intronic variant is not covered by the functional assay framework.	vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes
BS4	Not assessed	VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. No segregation data is available for this variant.
BP1	N/A	BP1 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications; truncating variants account for only a portion of disease-causing variants in TP53.	cspec
BP2	N/A	BP2 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications.	cspec
BP4	Met	SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00, which is ≤0.1), meeting the VCEP BP4_Supporting threshold for intronic variants.	spliceai cspec
BP5	N/A	BP5 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications.	cspec
BP6	N/A	BP6 is marked as Not Applicable by the TP53 VCEP v2.4.0 specifications, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Met	NM_000546.6:c.-29+102T>G is an intronic variant at position +102 (beyond +7) with SpliceAI max delta score of 0.00 (≤0.1), meeting the VCEP BP7_Supporting rule for intronic variants at or beyond +7 to -21 positions with no predicted splice impact.	spliceai cspec

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