Variant classification summary

NM_000546.6:c.919+4A>G

TP53 · NP_000537.3:p.? · NM_000546.6

GRCh37: chr17:7577015 T>C · GRCh38: chr17:7673697 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting BP4 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.919+4A>G is an intronic variant at the +4 position of intron 8 in TP53, evaluated under the ClinGen TP53 VCEP Specifications v2.4.0. The variant is absent from gnomAD v2.1 and v4.1, supporting PM2_Supporting.

2

SpliceAI predicts no splicing impact (max delta score 0.00). As an intronic variant outside the ±1,2 canonical splice positions with SpliceAI ≤0.1, BP4_Supporting is met.

3

PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice donor/acceptor positions addressed by the VCEP PVS1 flowchart. PS3/BS3 functional codes are not applicable as they address missense variants and small in-frame deletions only. The variant is not located in a VCEP-specified mutational hotspot and has no amino acid change, so PM1 and PM5 are not applicable.

4

With one pathogenic supporting code (PM2_Supporting, +1 point) and one benign supporting code (BP4_Supporting, -1 point), the total point value is 0. Under the Tavtigian point-based system adopted by the TP53 VCEP v2.4.0, a score of 0 falls in the range of Uncertain Significance (-1 to 5 points).

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of 0, 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.919+4A>G is an intronic variant at the +4 position, which is outside the canonical ±1,2 splice consensus. The TP53 VCEP PVS1 flowchart applies to canonical splice sites (±1,2 positions) only. SpliceAI predicts no splicing impact (max delta 0.00). PVS1 is not applicable to non-canonical intronic variants under the VCEP framework.	cspec spliceai
PS1	Not assessed	No other nucleotide substitutions at the c.919+4 position have been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. The VCEP PS1 rule requires a different nucleotide change at the same position previously determined to be pathogenic following VCEP specifications.	cspec
PS2	Not assessed	No de novo observations for NM_000546.6:c.919+4A>G were identified in the available literature. The VCEP PS2 rule requires proband points tallied using the LFS cancer scoring table, which requires proband-level clinical data.
PS3	N/A	The TP53 VCEP functional assay criteria (PS3/BS3) apply to missense variants and small in-frame deletions evaluated through protein function assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi). NM_000546.6:c.919+4A>G is an intronic variant that does not alter an amino acid and is not covered by the VCEP functional assay framework.	cspec vcep_functional_worksheet
PS4	Not assessed	No proband data with Li-Fraumeni syndrome-associated cancers were available for NM_000546.6:c.919+4A>G. The VCEP PS4 rule requires tallying proband cancer points (strongly associated cancers: 4 points; moderately associated: 2 points) against strength thresholds (Supporting: 1-1.5, Moderate: 2-3.5, Strong: 4-7.5, Very Strong: ≥8).	cspec
PS5	N/A	PS5 is not defined in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework.	cspec
PM1	N/A	The TP53 VCEP PM1 rule applies to missense variants within specified hotspot codons (175, 245, 248, 249, 273, 282) or missense variants with ≥10 somatic occurrences at the same amino acid change in cancerhotspots.org. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change.	cspec
PM2	Met	NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the TP53 VCEP PM2_Supporting threshold of allele frequency <0.00003 (0.003%).	gnomad_v2 gnomad_v4
PM5	N/A	The TP53 VCEP PM5 rule applies to missense variants at an amino acid residue where other missense variants have been determined to be pathogenic/likely pathogenic. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change, and the PM5 candidate search confirmed no eligible comparator variants.	cspec pm5_candidates
PM6	N/A	PM6 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework.	cspec
PP1	Not assessed	No cosegregation data were available for NM_000546.6:c.919+4A>G. The VCEP PP1 rule requires cosegregation observed in ≥3 meioses (Supporting), 5-6 meioses (Moderate), or ≥7 meioses (Strong) across one or more families.	cspec
PP2	N/A	PP2 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework.	cspec
PP3	Not met	For intronic splice variants outside the ±1,2 canonical positions, the TP53 VCEP PP3 rule requires SpliceAI ≥0.2. NM_000546.6:c.919+4A>G has a SpliceAI max delta score of 0.00, which does not meet this threshold. There is no predicted splicing impact.	cspec spliceai
PP4	Not assessed	No observations of NM_000546.6:c.919+4A>G with variant allele fraction (VAF) data were available. The VCEP PP4 rule requires one or more observations with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate).	cspec
PP5	N/A	PP5 is designated Not Applicable for This VCEP in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The TP53 VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in gnomAD continental subpopulations (excluding founder-influenced groups). NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 and v4.1, far below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The TP53 VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in gnomAD continental subpopulations. NM_000546.6:c.919+4A>G is absent from gnomAD v2.1 and v4.1, far below the BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No data were available on unrelated females ≥60 years of age without cancer carrying NM_000546.6:c.919+4A>G. The VCEP BS2 rule requires ≥2 such individuals from a single source (Supporting), 4-7 (Moderate), or ≥8 (Strong).	cspec
BS3	N/A	The TP53 VCEP functional assay criteria (PS3/BS3) apply to missense variants and small in-frame deletions evaluated through protein function assays. NM_000546.6:c.919+4A>G is an intronic variant with no amino acid change and is not covered by the VCEP functional assay framework.	cspec vcep_functional_worksheet
BS4	Not assessed	No segregation data were available to assess lack of segregation in affected family members. The VCEP BS4 rule requires lack of segregation in family members diagnosed with LFS-associated cancers.	cspec
BP1	N/A	BP1 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. The VCEP states this rule code does not apply to TP53, as truncating variants account for only a portion of disease-causing variants.	cspec
BP2	N/A	BP2 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework.	cspec
BP4	Met	NM_000546.6:c.919+4A>G is an intronic variant outside the ±1,2 canonical splice positions. Per the TP53 VCEP BP4 rule, intronic variants outside ±1,2 with SpliceAI ≤0.1 qualify for BP4_Supporting. The SpliceAI max delta score is 0.00, meeting this threshold.	cspec spliceai
BP5	N/A	BP5 is designated Not Applicable in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not available for use under the governing framework.	cspec
BP6	N/A	BP6 is designated Not Applicable for This VCEP in the ClinGen TP53 VCEP Specifications v2.4.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	The TP53 VCEP BP7_Supporting rule requires an intronic variant at or beyond +7 to -21 positions with SpliceAI ≤0.1 and BP4 met. NM_000546.6:c.919+4A>G is at the +4 position, which does not satisfy the 'at or beyond +7' requirement. BP7_Strong requires RNA splicing assay data demonstrating no splicing aberration, which is not available. BP7 criteria are not met.	cspec spliceai

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