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This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About TP53
TP53 encodes the p53 protein, a critical tumor suppressor that acts as a transcription factor to protect cells from damage. When activated by cellular stress such as DNA damage, p53 triggers responses including DNA repair, cell cycle arrest, and programmed cell death (apoptosis) to prevent the propagation of damaged cells. TP53 is the most frequently mutated gene in human cancers, and loss of its function contributes to tumor development, invasion, drug resistance, and genomic instability. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a rare hereditary condition that greatly increases the risk of developing multiple types of cancer at a young age.
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01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 3 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 not_met: c.919+17A>G is a deep intronic variant (intron 8, +17) with no predicted protein consequence (p.?); it is not a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or deletion null variant; the SpliceAI lookup returned no score; the variant is absent from the VCEP PVS1-Splicing-Worksheet (which assigns PVS1 (RNA) to c.919+1G>C/T/A); and no RNA-based functional evidence demonstrates a splicing alteration. TP53 LOF is an established mechanism, but this variant is not a demonstrated null allele.
PM4 not_applicable: TP53 VCEP CSPEC v2.4 declares PM4 Not Applicable, and the variant produces no protein length change (NP_000537.3:p.?).
BP3 not_applicable: TP53 VCEP CSPEC v2.4 declares BP3 Not Applicable; the generic ACMG BP3 (in-frame indels in repetitive regions without known function) does not apply to an intronic substitution with no protein change and no repeat-region context.
NM_000546.6:c.919+17A>G is an intronic substitution (intron 8, +17 position; VariantValidator exonic positions 8i) with predicted protein consequence NP_000537.3:p.? - it does not alter an amino acid residue.
All five criteria in this group (PS1, PM1, PM5, PP2, BP1) are residue- or missense-based, and none can apply to a variant with no amino acid consequence.
The governing ClinGen TP53 VCEP v2.4 CSPEC (framework_mode=vcep) explicitly declares PP2 and BP1 'Not Applicable' for TP53, and its PS1, PM1, and PM5 rules are all restricted to missense variants.
vcep_materials.json domain_tables contains no entry for TP53 (empty object), so no authoritative VCEP critical functional domain table was available for a residue-level PM1 check; PM1 was assessed from the CSPEC rule text, which requires a missense variant at hotspot codons 175/245/248/249/273/282 or with cancerhotspots.org somatic occurrences.
pm5_candidates.json corroborates that PM5 is not applicable (variant consequence class is not missense; 0 same-residue comparator candidates).
No published literature relevant to this group's criteria was identified; the three fetched papers (PMID:25741868, PMID:20065170, PMID:26324357) do not mention this variant and were not used to support any criterion here.
Governing framework: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 v2.4 (cspec), which takes precedence over generic ACMG/AMP for this gene.
PS2 (de novo), PP1 (cosegregation), and BS4 (lack of segregation) are applicable codes under the TP53 VCEP, but the case-evidence bundle contains no proband phenotype, parental testing results, maternity/paternity confirmation, or family segregation data; all three are therefore not_assessed pending clinical and family-level data.
PM6 is not applicable under TP53 VCEP v2.4, which explicitly dropped PM6 and uses PS2 exclusively for de novo evidence.
No publication in the case bundle mentions NM_000546.6:c.919+17A>G; the three full-text papers reviewed (PMID:20065170, PMID:25741868, PMID:26324357) contain no de novo, parental, or segregation evidence for this variant.
The ClinVar classification (Likely benign, 6 clinical laboratories) was not used to infer any segregation or de novo criterion, per adjudication rules.
Under the governing ClinGen TP53 VCEP specification v2.4, PS3 and BS3 are functional protein codes applied only to missense variants and small in-frame deletions, with pre-assigned strengths in the Functional worksheet keyed by amino acid change (Kato et al. PMID:12826609 primary; Giacomelli PMID:30224644, Kawaguchi PMID:16007150, Kotler PMID:29979965, Funk PMID:39774325 as eligible supporting assays).
NM_000546.6:c.919+17A>G is a deep intronic variant (intron 8, +17) with no amino acid consequence (NP_000537.3:p.?), so it has no entry in the Functional worksheet and none of the VCEP PS3/BS3 protein-function strength rules can be evaluated; both codes are assessed as not_applicable for this variant type.
No functional assay evidence of any kind is available for this variant in the case bundle: no Kato/Giacomelli/Kawaguchi/Kotler/Funk protein data (not applicable to intronic variants), no RNA-based splicing assay data (RNA-seq/minigene/RT-PCR), and the SpliceAI lookup returned no score.
Per the VCEP v2.4 caveat, any future laboratory evidence of splicing aberration for this variant would be evaluated via PVS1_Variable Weight (RNA), and RNA evidence of no splicing aberration would be evaluated via BP7_Strong (Walker et al. 2023, PMID:37352859) in the splicing group - not via PS3/BS3.
The ClinVar 'Likely benign' classification by six clinical laboratories was not used to infer any functional criterion, consistent with the requirement not to derive criteria from other sources' final classifications.
Governing framework: ClinGen TP53 VCEP specifications v2.4 (cspec), which takes precedence over generic ACMG/AMP for TP53.
PS4 and PP4 are applicable codes under the VCEP but cannot be assessed: the case bundle contains no proband phenotype/clinical-criteria data (needed for the PS4 points system) and no low-VAF MGPT observation data (needed for PP4).
PP5, BP5, and BP6 are declared Not Applicable by the TP53 VCEP v2.4; the global PP5/BP6 override (exact-variant ClinVar expert-panel classification) does not apply because VCV000378747 has zero expert-panel submissions and its Likely benign label comes only from ordinary clinical laboratories.
No publication retrieved for this case mentions c.919+17A>G, so no literature-based case-control, phenotype, or reputable-source evidence is available for this group.
Both allelic criteria (PM3, BP2) are excluded by the governing TP53 VCEP v2.4 framework (framework_mode = vcep), so neither contributes evidence to the classification.
PM3: not applicable — TP53/Li-Fraumeni syndrome is autosomal dominant, and the VCEP explicitly states the rule does not apply to TP53/Li-Fraumeni syndrome.
BP2: not applicable — TP53 VCEP v2.4 cspec flags BP2 'Not Applicable' with all strength rules not applicable; no trans/cis phase evidence exists in the case bundle in any case.
No phase-resolved (trans/cis) observations of c.919+17A>G with a pathogenic/likely pathogenic TP53 variant are documented anywhere in the case evidence bundle (ClinVar submissions carry no phase data; fetched papers do not mention the variant).
Governing framework: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 (cspec, precedence rank 1); generic ACMG/AMP 2015 rules were not used because a gene-specific VCEP specification exists.
Variant class: intronic single-nucleotide substitution at exon 8 donor +17 (NC_000017.10:g.7577002T>C / NC_000017.11:g.7673684T>C), outside the +/-1,2 splice consensus positions, with no predicted protein consequence (NP_000537.3:p.?).
For intronic variants outside +/-1,2, the TP53 VCEP assigns PP3 (SpliceAI >= 0.2), BP4 (SpliceAI <= 0.1), and BP7 supporting (intronic at >=+7 to -21 with SpliceAI <= 0.1) all on the basis of the SpliceAI max delta score; the BayesDel/aGVGD missense pathways do not apply to this variant type.
The SpliceAI score for this variant is unavailable: the SpliceAI Lookup scrape returned no result ('No SpliceAI score returned from API') and no pre-assigned SpliceAI or PP3/BP4 entry exists in the VCEP PP3-BP4-codes.xlsx or PVS1-Splicing-Worksheet.xlsx lookup tables (verified by direct read).
Consequently PP3, BP4, and BP7 are all not_assessed; a human reviewer should obtain the SpliceAI max delta score (re-run SpliceAI Lookup or inspect the saved spliceai.png screenshot) to resolve these codes. No RNA splicing assay data exists for BP7_Strong.
Governing framework: ClinGen TP53 Expert Panel (VCEP) Specifications v2.4 (cspec); generic ACMG/AMP was not used because an applicable VCEP specification exists for all four population criteria.
BA1 not met: grpmax FAF 2.8e-07 and highest eligible group AF ~1.7e-06 (NFE) are far below the VCEP stand-alone threshold of 0.001.
BS1 not met: highest eligible group AF ~1.7e-06 (NFE, 2 alleles) is far below the VCEP strong-benign threshold of 0.0003.
PM2_Supporting met: gnomAD v4.1 total AF 1.85856e-06 (< 0.00003), NFE group AF 1.69485e-06 (< 0.00004 with 2 alleles), 0 homozygotes; absent from gnomAD v2.1 and gnomAD-Canada.
BS2 not assessed: no single-source data on unrelated female carriers >= 60 years without cancer is available in the case evidence bundle; this is a data-collection gap, not a demonstration that the criterion is unmet.
No literature source in this case mentions the variant or provides population-frequency data for it (see paper_findings).
No criteria match.
Met · 1
PM2SupportingMet (supporting): gnomAD v4.1 allele frequency 1.86e-06 (3/1,614,156 alleles), well below the <0.003% PM2 threshold.
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Reasoning
Under the ClinGen TP53 VCEP v2.4 (cspec) specification, PM2 is applied at supporting strength when the allele frequency is < 0.00003 (0.003%) in gnomAD or another large sequenced population, and, if multiple alleles are present within any genetic ancestry group, the group-specific frequency is < 0.00004 (0.004%); founder-effect groups (Ashkenazi Jewish, Finnish, Amish, Middle Eastern, Remaining) are ignored. For c.919+17A>G, gnomAD v4.1 total AF is 1.85856e-06 (3/1,614,156 alleles), well below 0.00003. The only non-excluded group with multiple alleles is European non-Finnish (2/1,180,044; AF 1.69485e-06), below 0.00004. No homozygotes are observed, and the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The PM2 CHIP-recalculation clause (for variants with total AF > 0.00003 that meet no population rule) is not triggered because total AF is below 0.00003. PM2_Supporting is met.
Rule
TP53 VCEP v2.4 PM2 (Supporting): allele frequency < 0.00003 (0.003%) in gnomAD or another large sequenced population; if multiple alleles are present within any genetic ancestry group, group AF must be < 0.00004 (0.004%); founder-effect groups ignored.
Evidence considered
ClinGen TP53 VCEP v2.4 PM2 rule (cspec): apply at supporting level when allele frequency is < 0.00003 (0.003%) in gnomAD or another large sequenced population; if multiple alleles are present within any genetic ancestry group, the group AF must be < 0.00004 (0.004%); founder-effect groups (Ashkenazi Jewish, Finnish, Amish, Middle Eastern, 'Remaining') are ignored.
gnomAD v4.1 (17-7673684-T-C): total AF 1.85856e-06 (0.000186%; 3/1,614,156 alleles), 0 homozygotes; European non-Finnish is the only non-excluded group with >= 2 alleles (2/1,180,044; AF 1.69485e-06, 0.000169%, below 0.004%); Remaining individuals (1/62,506; AF 1.59985e-05) is excluded by rule; grpmax FAF 2.8e-07.
gnomAD v2.1 (17-7577002-T-C) and gnomAD-Canada v1.0: variant absent, consistent with extreme rarity.
Total AF (1.86e-06) is below the 0.00003 PM2 threshold and the only multi-allele eligible group (NFE) is below the 0.00004 group threshold, so the CHIP/VAF-recalculation clause (applicable only when total AF > 0.00003) is not triggered; allele-balance histogram data was not captured but is not required here.
No homozygotes in gnomAD v4.1 (0/1,614,156), consistent with absence of homozygosity for this allele.
PVS1Not met: this intronic substitution at +17 has no predicted protein change and lies outside the canonical splice sites, so it is not a null variant.
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Reasoning
TP53 germline loss of function is an established disease mechanism (gene-level PVS1 gate eligible per pvs1_gene_context), but variant NM_000546.6:c.919+17A>G is not a null variant: it is an intronic substitution 17 nucleotides into intron 8 (between exons 8 and 9), outside the canonical +/-1,2 splice consensus (canonical_splice_consensus=false), and its predicted protein consequence is p.? (no protein-level change). The TP53 VCEP CSPEC v2.4 PVS1 decision tree limits PVS1 to initiation-codon variants, nonsense/frameshift premature-termination-codon variants (with NMD-position-dependent strengths relative to p.Lys351), canonical splice variants, and single/multi-exon deletions; a deep intronic +17 variant is in none of these categories. No computational or experimental evidence of a splicing alteration exists: the SpliceAI lookup for this variant returned no score (search_status=no_result), and the VCEP PVS1-Splicing-Worksheet (Supplementary Table S1) assigns PVS1 (RNA) to the exon 8 donor variants c.919+1G>C/T/A (SpliceAI 0.47-0.52, exon 8 skipping / intron 8 retention, both PTC/NMD) but contains no entry for c.919+17A>G and no MutSpliceDB record. Per ACMG/AMP 2015 (PMID:25741868), confirmation of splice impact requires RNA- or protein-based functional analysis; no such confirmation is available, so PVS1 is not met.
Rule
TP53 VCEP CSPEC v2.4 (PVS1 decision tree / Figure 1, transcript NM_000546.6): PVS1 applies to initiation-codon variants; nonsense or frameshift-induced PTCs upstream of p.Lys351 predicted to undergo NMD (PVS1), p.Lys351-p.Ala355 not predicted NMD (PVS1_Strong), p.Gly356-p.Asp393 (PVS1_Moderate); canonical +/-1,2 splice variants with predicted splicing alterations; and single/multi-exon deletions. Splicing-based PVS1 requires SpliceAI and/or experimental RNA evidence.
Evidence considered
Variant NM_000546.6:c.919+17A>G is intronic, 17 nt into intron 8 (between exons 8 and 9); normalized protein consequence is NP_000537.3:p.? - no protein-level change predicted; VariantValidator classifies it as a gene variant in the intronic region (start/end exon 8i) of MANE Select transcript NM_000546.6.
TP53 VCEP CSPEC v2.4 PVS1 rule: 'Please utilize the PVS1 decision tree for application of PVS1 code' - PVS1 applies to initiation codon variants, nonsense/frameshift PTCs (NMD-position-dependent strengths relative to p.Lys351), canonical +/-1,2 splice variants, and single- to multi-exon deletions; this intronic +17 variant falls in none of these categories.
pvs1_gene_context.json: TP53 germline LOF is an established mechanism (official CSPEC/VCEP criteria include PVS1 guidance); PVS1 gene gate 'eligible' - this confirms LOF mechanism but does not make an intronic +17 variant a null allele.
pvs1_variant_assessment.json: consequence_class='unknown', canonical_splice_consensus=false, variant_bucket='other'; apply_generic_pvs1_framework=false with rationale that the variant does not fall into the generic null-variant buckets (nonsense, frameshift, canonical +/-1,2 splice).
SpliceAI lookup (spliceailookup.broadinstitute.org) for NM_000546.6:c.919+17A>G returned no score (search_status=no_result, warning 'No SpliceAI score returned from API'); predicted splicing impact is unverified.
VCEP PVS1-Splicing-Worksheet.xlsx Supplementary Table S1 lists exon 8/intron 8 splice variants with SpliceAI scores and PVS1 strengths, e.g. c.919+1G>C (SpliceAI 0.49), c.919+1G>T (0.52), c.919+1G>A (0.47), each assigned PVS1 (RNA) with exon 8 skipping (Δ(E8)) and intron 8 retention (▼I8) both PTC/NMD; c.919+17A>G is not present in the table.
VCEP PVS1-Flowchart.pdf Figure 1 (transcript NM_000546.6) routes only null variants (nonsense, frameshift, canonical splice, initiation codon, deletions) through NMD-position-dependent PVS1 strengths; there is no branch for deep intronic variants without a demonstrated splicing alteration.
PMID:25741868 (ACMG/AMP 2015): 'For splice site variants, the variant may lead to exon skipping, shortening or inclusion of intronic material... confirmation of impact requires functional analysis by either RNA or protein analysis' - no such functional confirmation exists for c.919+17A>G, so a splicing-based PVS1 cannot be applied.
ClinVar 'Likely benign' classification (6 clinical laboratories, VCV000378747) was noted in the case file but was NOT used as evidence for PVS1 in this group, consistent with the rule against deriving a criterion from another source's final classification.
Still missing
SpliceAI lookup for NM_000546.6:c.919+17A>G returned no score (API no_result) - predicted splicing impact could not be verified computationally
No RNA-based assay data (patient RNA, minigene, or MutSpliceDB entry) available to exclude or confirm a splicing effect of this +17 intronic variant
Variant not present in the VCEP PVS1-Splicing-Worksheet Table S1, so no pre-assigned VCEP PVS1 strength exists for it
BA1Not met: highest eligible group frequency ~1.7e-06, about 600-fold below the >=0.1% BA1 threshold.
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Reasoning
Under the ClinGen TP53 VCEP v2.4 (cspec) specification, BA1 (stand-alone benign) requires a filtering allele frequency (FAF) of >= 0.001 (0.1%) in gnomAD continental subpopulations of a single genetic ancestry group, excluding founder-effect groups (Ashkenazi Jewish, Finnish, Amish, Middle Eastern, Remaining), with >= 2,000 alleles tested and a minimum of 2 alleles present. In gnomAD v4.1, c.919+17A>G has total AF 1.85856e-06 (3/1,614,156 alleles), 0 homozygotes, and grpmax FAF 2.8e-07. The highest subpopulation frequency is in Remaining individuals (AF 1.59985e-05, 1/62,506), a group excluded from BA1 application; the highest eligible group is European non-Finnish (AF 1.69485e-06, 2/1,180,044). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The highest eligible group FAF (~1.7e-06) is roughly 600-fold below the 0.001 threshold, so BA1 is not met. The allele-balance (VAF < 0.35) caution in the rule is not triggered because no group approaches the FAF cutoff.
Rule
TP53 VCEP v2.4 BA1: FAF >= 0.001 (0.1%) in gnomAD continental subpopulations of a single genetic ancestry group (excluding founder-effect groups: Ashkenazi Jewish, Finnish, Amish, Middle Eastern, Remaining); group must have >= 2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
ClinGen TP53 VCEP v2.4 BA1 rule (cspec): stand-alone benign requires gnomAD continental-subpopulation FAF >= 0.001 (0.1%) in a single genetic ancestry group, excluding founder-effect groups (Ashkenazi Jewish, Finnish, Amish, Middle Eastern, 'Remaining'), with >= 2,000 alleles tested and a minimum of 2 alleles present.
gnomAD v4.1 (17-7673684-T-C): total AF 1.85856e-06 (3/1,614,156 alleles), 0 homozygotes; grpmax FAF 2.8e-07; highest subpopulation frequency in Remaining individuals (AF 1.59985e-05, 1/62,506 alleles, 0 homozygotes; group excluded by the VCEP rule); European non-Finnish AF 1.69485e-06 (2/1,180,044 alleles, 0 homozygotes); all other continental groups have 0 alleles.
BS1Not met: highest eligible group frequency 1.7e-06, about 180-fold below the >=0.03% BS1 threshold.
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Reasoning
Under the ClinGen TP53 VCEP v2.4 (cspec) specification, BS1 (strong benign) requires a FAF of >= 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (same founder-effect exclusions, >= 2,000 alleles, minimum 2 alleles). For c.919+17A>G, the highest eligible group frequency is European non-Finnish at AF 1.69485e-06 (2/1,180,044); the Remaining individuals group (AF 1.59985e-05) is excluded as founder-influenced. grpmax FAF is 2.8e-07 and the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. The highest eligible group AF is roughly 180-fold below the BS1 lower bound of 0.0003, so BS1 is not met.
Rule
TP53 VCEP v2.4 BS1: FAF >= 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding founder-effect groups: Ashkenazi Jewish, Finnish, Amish, Middle Eastern, Remaining); group must have >= 2,000 alleles tested and a minimum of 2 alleles present.
Evidence considered
ClinGen TP53 VCEP v2.4 BS1 rule (cspec): strong benign requires gnomAD continental-subpopulation FAF >= 0.0003 but < 0.001 in a single genetic ancestry group (excluding founder-effect groups: Ashkenazi Jewish, Finnish, Amish, Middle Eastern, 'Remaining'), with >= 2,000 alleles tested and a minimum of 2 alleles present; the cutoff was derived via a Whiffin-Ware calculation (LFS prevalence 1 in 5,000, PMID 16644204 referenced in the VCEP).
gnomAD v4.1: total AF 1.85856e-06 (3/1,614,156 alleles); European non-Finnish AF 1.69485e-06 (2/1,180,044 alleles, the only eligible group with >= 2 alleles); Remaining individuals AF 1.59985e-05 (1/62,506, excluded by rule); 0 homozygotes; grpmax FAF 2.8e-07.
gnomAD v2.1 and gnomAD-Canada v1.0: variant absent.
Highest eligible group AF (~1.7e-06) is about 180-fold below the BS1 threshold of 0.0003; therefore BS1 is not met.
PS2Not assessed: no proband phenotype, parental testing, or maternity/paternity confirmation is available to establish a de novo event.
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Reasoning
PS2 is applicable under the ClinGen TP53 VCEP v2.4 specifications (cspec): de novo points are tallied per proband using the Table of LFS Cancers and Points for PS2 and PP1 Code Application (strongly associated LFS cancer = 4 points, moderately associated = 2 points), with PS2_Supporting at 1 point, PS2_Moderate at 2-3 points, PS2 at 4-7 points, and PS2_Very Strong at >=8 points; maternity and paternity must be confirmed (confirmed constitutional mosaics may count as confirmed de novo). The consolidated case-evidence bundle contains no proband phenotype or cancer history, no parental testing results, and no maternity/paternity confirmation for c.919+17A>G, so no de novo observation can be established. PS2 is therefore not_assessed pending proband and parental data.
Rule
TP53 VCEP v2.4: de novo points per proband (strongly associated LFS cancer 4 pts, moderately associated 2 pts); strength by total points (1 = Supporting, 2-3 = Moderate, 4-7 = Strong, >=8 = Very Strong).
Evidence considered
ClinGen TP53 VCEP v2.4 (cspec) PS2 rule: de novo points per proband (strongly associated LFS cancer 4 pts, moderately associated 2 pts; use highest-weight cancer for probands with multiple cancers); PS2_Supporting = 1 pt, PS2_Moderate = 2-3 pts, PS2 = 4-7 pts, PS2_Very Strong = >=8 pts; confirmed constitutional mosaics may be counted as confirmed de novo.
TP53 VCEP PS2/PP1 table (Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf) provides the cancer point values and PS2 strength thresholds referenced by the PS2 rule.
No source in the case bundle documents a de novo occurrence of NM_000546.6:c.919+17A>G; ClinVar submissions for VCV000378747 contain no de novo or parental-testing information and were not used to infer this criterion.
Still missing
No proband phenotype/cancer history in the case bundle to assign PS2 points.
No parental testing results or maternity/paternity confirmation for c.919+17A>G.
PS4Not assessed: no proband phenotype or case-control data exists to tally PS4 points.
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Reasoning
The TP53 VCEP v2.4 PS4 rule is points-based: per proband, Revised Chompret criteria = 0.5 pt, Classic LFS criteria = 1 pt, HER2+ breast cancer <40 y = 0.5 pt, with strength thresholds of Supporting 1-1.5 pts, Moderate 2-3.5 pts, Strong 4-7.5 pts, Very Strong >=8 pts. Awarding any points requires proband clinical/phenotype data (cancer type and age, Chompret/LFS criteria status). The case bundle contains no proband phenotype, cancer history, or case-control data for c.919+17A>G, so no points can be tallied and PS4 cannot be assessed. The ClinVar Likely benign aggregate label is not proband phenotype evidence and must not be used to infer anything about PS4. None of the full-text papers retrieved for this case mention the variant.
TP53 VCEP v2.4 (cspec) defines PS4 as applicable with a points system: Revised Chompret = 0.5 pt, Classic LFS = 1 pt, HER2+ breast cancer <40 y = 0.5 pt per proband; PS4_Supporting 1-1.5 pts, PS4_Moderate 2-3.5 pts, PS4 4-7.5 pts, PS4_Very Strong >=8 pts; probands with de novo variants should use PS2 instead.
PS4-Points-Table.pdf in the VCEP materials lists the same per-proband point values and strength thresholds.
review_manifest.json, case_summary.json, and evidence.json contain no proband phenotype, cancer history, or case-control data for this variant.
Full-text papers retrieved as PS4/PP5 candidates (PMID:20065170, PMID:26324357) do not mention c.919+17A>G and provide no case observation data for it.
Still missing
No proband phenotype data: Classic LFS / Revised Chompret criteria status of any carrier of c.919+17A>G is unavailable
No case-control enrichment data: variant frequency in affected (LFS-spectrum cancer) versus control cohorts is unavailable
No HER2+ breast cancer <40 y or other LFS-associated cancer data for any carrier
PP1Not assessed: no family segregation studies or meiosis counts are available.
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Reasoning
PP1 is applicable under the ClinGen TP53 VCEP v2.4 specifications (cspec): meioses are counted for individuals who carry the variant and have a relevant LFS-associated cancer (Table of LFS Cancers and Points for PS2 and PP1 Code Application), with PP1_Supporting at 3-4 meioses, PP1_Moderate at 5-6 meioses, and PP1_Strong at >=7 meioses across >1 family; PP1 should not be applied if BA1/BS1 are met. The case bundle contains no family segregation studies, no affected relatives tested for c.919+17A>G, and no meioses count, so cosegregation cannot be established. PP1 is therefore not_assessed pending segregation data. (BA1/BS1 are not met - gnomAD v4.1 AF 1.86e-06, grpmax FAF 2.8e-07 - so that exclusion does not apply, but no positive segregation evidence exists either.)
Rule
TP53 VCEP v2.4: cosegregation in carriers with LFS-associated cancers; 3-4 meioses = Supporting, 5-6 = Moderate, >=7 across >1 family = Strong.
Evidence considered
ClinGen TP53 VCEP v2.4 (cspec) PP1 rule: meioses counted for carriers with a relevant LFS-associated cancer (meioses through unaffected obligate carriers allowed); PP1_Supporting = 3-4 meioses, PP1_Moderate = 5-6 meioses, PP1_Strong = >=7 meioses across >1 family; do not apply PP1 if BA1/BS1 are met.
TP53 VCEP PS2/PP1 table defines the LFS-associated cancers used for PP1 meioses counting.
No literature or database source in the case bundle reports cosegregation of c.919+17A>G with LFS-associated cancer in any family; the full-text papers reviewed (PMID:20065170, PMID:25741868, PMID:26324357) do not mention this variant.
BA1/BS1 are not met (gnomAD v4.1 total AF 1.85856e-06, grpmax FAF 2.8e-07; absent from gnomAD v2.1), so the VCEP PP1 exclusion does not apply; however, absence of segregation data precludes PP1 application.
Still missing
No family segregation studies or meioses count available for c.919+17A>G.
No genotype-phenotype data for affected relatives carrying the variant.
PP3Not assessed: no SpliceAI score was available to test the required >=0.2 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
NM_000546.6:c.919+17A>G is an intronic variant at the exon 8 donor +17 position, outside the +/-1,2 splice consensus positions. Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), the only applicable PP3 pathway for this variant type is the intronic splice variant rule: PP3 (supporting) requires a SpliceAI max delta score >= 0.2 for intronic variants excluding +/-1,2 positions. The missense BayesDel/aGVGD pathway does not apply because the variant has no protein consequence (p.?). The SpliceAI Lookup attempt in this case returned no score (evidence.json spliceai: search_status 'no_result', warning 'No SpliceAI score returned from API', scores empty, max_delta null), and neither the VCEP PP3-BP4-codes.xlsx (Supplementary Table S2, which covers only predicted missense variants) nor the PVS1-Splicing-Worksheet.xlsx (Table S1, which covers only +/-1,2 GT-AG variants) contains a pre-assigned PP3/BP4 code or SpliceAI score for c.919+17A>G (verified by direct read of both spreadsheets). Without a SpliceAI score, PP3 (>= 0.2) can be neither confirmed nor refuted, so the criterion is not assessed. A human reviewer should obtain the SpliceAI max delta score (e.g., re-run the SpliceAI Lookup or read the saved spliceai.png screenshot) before this code can be resolved.
Variant is intronic at exon 8 donor +17, so the missense BayesDel/aGVGD PP3 pathways (BayesDel >= 0.16 with aGVGD C25-C55 or C65) are not applicable; no protein consequence is predicted (p.?).
SpliceAI Lookup (source_registry key 'spliceai') returned no score for NM_000546.6:c.919+17A>G: evidence.json records search_status 'no_result' and warning 'No SpliceAI score returned from API'; case_summary spliceai block has empty scores and max_delta null.
Direct read of vcep_db/TP53/files/PP3-BP4-codes.xlsx (Supplementary Table S2, 2573 rows) found no entry containing 'c.919+17'; the table covers only predicted missense variants and notes SpliceAI must be considered separately.
Direct read of vcep_db/TP53/files/PVS1-Splicing-Worksheet.xlsx (Table S1, 1060 rows) found no entry for c.919+17A>G; the sheet covers GT-AG +/-1,2 splice site variants only.
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable (SpliceAI Lookup returned no result); PP3 supporting for intronic variants outside +/-1,2 requires SpliceAI >= 0.2.
No pre-assigned PP3/BP4 code for c.919+17A>G exists in the VCEP PP3-BP4-codes.xlsx or PVS1-Splicing-Worksheet.xlsx lookup tables.
PP4Not assessed: no multigene-panel variant allele fraction (VAF 5-35%) observation is available for this variant.
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Reasoning
The TP53 VCEP v2.4 PP4 rule applies only to observations of the variant at low variant allele fraction (VAF 5-35%) on multigene panel testing, reflecting likely somatic origin (CHIP/mosaic) rather than germline disease; Supporting = observation with VAF 5-35%, Moderate = at least 2 independent observations with VAF 5-25%. The case bundle contains no patient-level VAF observation for c.919+17A>G on any panel test; gnomAD population allele counts are population frequencies, not MGPT VAF observations, and cannot substitute. PP4 therefore cannot be assessed.
Rule
TP53 VCEP v2.4 PP4: Supporting = observation with VAF 5-35% on MGPT; Moderate = >=2 independent observations with VAF 5-25%. Assumes somatic origin; excluded for blood-cancer patients and when BA1/BS1 met.
Evidence considered
TP53 VCEP v2.4 (cspec) PP4: Supporting = observation of the variant with VAF 5-35% (once with VAF 5-25% and/or VAF >25-35%); Moderate = at least 2 independent observations with VAF 5-25%; the code assumes somatic origin, requires detection on multigene panel testing, must not be applied in patients with blood cancer, and must not be applied if BA1/BS1 are met.
No variant allele fraction data for c.919+17A>G is reported in any source in the case bundle (review_manifest, case_summary, prefetch, evidence).
gnomAD v4.1 population frequencies (3/1,614,156 alleles) are population-level counts and are not PP4 VAF observations.
Still missing
No MGPT observation of c.919+17A>G with a reported VAF (Supporting requires VAF 5-35%; Moderate requires >=2 independent observations with VAF 5-25%)
No data on tissue origin of any observation (blood vs tumor vs non-lymphocyte tissue) needed to distinguish somatic origin from constitutional mosaicism
No RNA or confirmatory data excluding CHIP/technical artifact for any observation
BS2Not assessed: no source provides counts of unaffected women aged 60 or older without cancer.
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Reasoning
The ClinGen TP53 VCEP v2.4 BS2 rule requires 2-3 unrelated females who reached at least 60 years of age without cancer (Supporting), 4-7 (Moderate), or >= 8 (Strong), all from a single source (single lab/database), excluding individuals with sarcoma diagnosed at >= 61 years and carriers with VAF <= 35% (suggestive of somatic origin). No source in this case provides the required per-individual data: gnomAD reports only aggregate allele counts with no age/sex/phenotype annotation, and the ClinVar submissions (6 clinical laboratories, all germline 'Likely benign') do not report counts of unaffected elderly female carriers and cannot be used as evidence for this criterion (classifications are not population evidence). Therefore BS2 cannot be assessed from the available evidence and is returned as not_assessed pending cohort-level data.
Rule
TP53 VCEP v2.4 BS2: >= 8 unrelated females who have reached at least 60 years of age without cancer from a single source = Strong; 4-7 = Moderate; 2-3 = Supporting. Individuals with sarcoma diagnosed at >= 61 years are not counted; VAF <= 35% (somatic-origin suggestive) carriers are excluded.
Evidence considered
ClinGen TP53 VCEP v2.4 BS2 rule (cspec): 2-3 unrelated females >= 60 years without cancer from a single source = BS2_Supporting; 4-7 = BS2_Moderate; >= 8 = BS2_Strong; individuals with sarcoma diagnosed at >= 61 years are excluded, and carriers with VAF <= 35% (suggestive of somatic origin) are not counted; cases cannot be pooled across sources.
Case evidence bundle contains no cohort, pedigree, or registry data with age/sex/cancer-status for carriers of c.919+17A>G (gnomAD v4.1 provides aggregate allele counts only, 3/1,614,156, no phenotype annotation; ClinVar lists 6 germline submissions classified Likely benign but provides no unaffected-elderly-female counts).
ClinVar final classifications were not used as evidence for BS2 (never infer a criterion from another source's final classification).
Still missing
No single-source (single lab or database) data documenting unrelated female carriers of c.919+17A>G who reached at least 60 years of age without cancer; such multigene-panel cohort counts (e.g., per the VCEP's derivation from two diagnostic labs) would be required to assess BS2 at any strength.
BS4Not assessed: no family testing data exists to demonstrate lack of segregation in affected relatives.
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Reasoning
BS4 is applicable under the ClinGen TP53 VCEP v2.4 specifications (cspec) at Strong: it requires demonstrated lack of segregation in affected family members (family members diagnosed with LFS-associated cancers as described in the Table of LFS Cancers and Points for PS2 and PP1 Code Application). The case bundle contains no family segregation data at all - no affected family members tested, no non-segregation observations - so lack of segregation cannot be established. BS4 is therefore not_assessed pending family testing data. The presence of the variant at very low frequency in gnomAD v4.1 (AF 1.86e-06) does not by itself satisfy or refute BS4, which is strictly a family segregation criterion under this VCEP.
Rule
TP53 VCEP v2.4: BS4 (Strong) = lack of segregation in affected family members with LFS-associated cancers.
Evidence considered
ClinGen TP53 VCEP v2.4 (cspec) BS4 rule (Strong): 'Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).'
No source in the case bundle reports testing of affected family members for c.919+17A>G, so no non-segregation evidence exists to support BS4.
ClinVar VCV000378747 submissions (6 clinical laboratories, Likely benign) contain no segregation information and their classifications were not used to infer BS4.
gnomAD v4.1 shows the variant at total AF 1.85856e-06 (grpmax FAF 2.8e-07, 0 homozygotes); population frequency is not family segregation evidence under the TP53 VCEP BS4 rule.
Still missing
No affected-family-member testing results available to assess segregation or lack thereof.
BP4Not assessed: no SpliceAI score was available to test the required <=0.1 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), BP4 (supporting) for 'Silent or Intronic Variants (outside +/- 1,2 positions)' requires SpliceAI <= 0.1. c.919+17A>G is an intronic variant at +17 (outside +/-1,2), so this is the only applicable BP4 pathway; the missense BayesDel pathways (BP4_Moderate: BayesDel <= -0.008; BP4: BayesDel < 0.16 and > -0.008, both with SpliceAI < 0.2) do not apply to an intronic variant with no protein consequence. The SpliceAI score is unavailable in this case (SpliceAI Lookup returned no result; warning 'No SpliceAI score returned from API'), and the VCEP lookup spreadsheets contain no pre-assigned entry for c.919+17A>G. Because SpliceAI <= 0.1 can be neither confirmed nor refuted, BP4 is not assessed. Human review is needed to obtain the SpliceAI score before applying BP4.
Rule
Silent or intronic variants (outside +/-1,2 positions): BP4 (supporting) if SpliceAI <= 0.1 (ClinGen TP53 VCEP Specifications v2.4).
Variant is intronic at +17 with no predicted protein consequence, so the missense BayesDel BP4 pathways are not applicable.
SpliceAI Lookup (source_registry key 'spliceai') returned no score: evidence.json records search_status 'no_result' and warning 'No SpliceAI score returned from API'; case_summary spliceai block has empty scores and max_delta null.
Direct read of vcep_db/TP53/files/PP3-BP4-codes.xlsx found no entry for c.919+17A>G (table covers predicted missense variants only).
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable; BP4 supporting for intronic variants outside +/-1,2 requires SpliceAI <= 0.1.
No pre-assigned BP4 code for c.919+17A>G exists in the VCEP PP3-BP4-codes.xlsx lookup table.
BP7Not assessed: no SpliceAI score to confirm the <=0.1 requirement, and no RNA assay data are available. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), BP7 (supporting) applies to 'an intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI <= 0.1)'. c.919+17A>G is at +17, satisfying the positional requirement, and no nucleotide-conservation assessment is required per the VCEP rule (per Walker et al. 2023, PMID 37352859 as cited in the rule). However, the SpliceAI score is unavailable (SpliceAI Lookup returned no result; warning 'No SpliceAI score returned from API'), so the SpliceAI <= 0.1 requirement cannot be confirmed. The stronger BP7_Strong pathway requires RNA splicing assay data demonstrating no splicing aberration; no RNA assay data for this variant is present in the case evidence bundle, so BP7_Strong is not met. BP7 is therefore not assessed pending retrieval of the SpliceAI score.
Rule
BP7 (supporting): intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 met, SpliceAI <= 0.1); BP7_Strong: RNA splicing assay data demonstrates no splicing aberration (ClinGen TP53 VCEP Specifications v2.4).
Evidence considered
TP53 VCEP v2.4 BP7 rule (supporting): intronic variant at or beyond +7 to -21 positions with SpliceAI predicting no impact (SpliceAI <= 0.1, i.e., BP4 met); no conservation assessment required per Walker et al. 2023 (PMID 37352859) as cited in the rule.
Variant position: intronic +17 relative to exon 8 donor, which is within the '+7 to -21' window, satisfying the positional component of BP7 supporting.
SpliceAI Lookup (source_registry key 'spliceai') returned no score for NM_000546.6:c.919+17A>G (evidence.json search_status 'no_result', warning 'No SpliceAI score returned from API').
BP7_Strong requires RNA splicing assay data demonstrating no splicing aberration; no RNA-based assay data for this variant was found in the case evidence bundle (evidence.json, literature_pass.json, paper_extracts.json reviewed).
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable; BP7 supporting requires SpliceAI <= 0.1 (BP4 met).
No RNA splicing assay data is available for this variant, so the BP7_Strong pathway (RNA assay demonstrates no splicing aberration, per Walker et al. 2023, PMID 37352859 as cited in the VCEP rule) cannot be evaluated.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: the rule requires the same amino acid change as a known pathogenic variant, and this variant has no amino acid change (p.?).
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Reasoning
The TP53 VCEP v2.4 CSPEC PS1 rule requires the variant to produce the same amino acid change as a previously established pathogenic or likely pathogenic variant (asserted per the VCEP's specifications, with splicing ruled out via RNA data or SpliceAI < 0.2). NM_000546.6:c.919+17A>G is a deep intronic substitution (17 bp downstream of exon 8, VariantValidator intronic positions 8i) with predicted protein consequence NP_000537.3:p.? — there is no amino acid change to compare, so PS1 cannot apply to this variant.
Rule
TP53 VCEP v2.4 CSPEC PS1 (Strong for Pathogenic comparator, Moderate for Likely Pathogenic comparator) - requires an identical amino acid change.
Evidence considered
TP53 VCEP v2.4 CSPEC PS1 rule: same amino acid change as a previously established pathogenic (Strong) or likely pathogenic (Moderate) variant per the VCEP's specifications; applies to missense variants with an amino acid change.
VariantValidator confirms NM_000546.6:c.919+17A>G is intronic (exon 8i) with predicted protein consequence NP_000537.3:p.? (no amino acid change).
Still missing
RNA or splicing-effect characterization of c.919+17A>G is not available, but this is not required for PS1 since the variant has no amino acid consequence.
PS3N/ANot applicable: PS3 requires functional assay results for a specific amino acid change, and this intronic variant has no protein consequence (p.?).
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Reasoning
The governing ClinGen TP53 VCEP specification v2.4 defines PS3 exclusively through protein-function assay results keyed to a specific amino acid change (Kato et al. 2003, PMID:12826609, primary assay; complemented by Giacomelli et al. 2018 PMID:30224644, Kawaguchi et al. 2005 PMID:16007150, Kotler et al. 2018 PMID:29979965, Funk et al. 2025 PMID:39774325), applied to missense variants and small in-frame deletions per the functional rule-codes flowchart and Functional worksheet (Supplementary Table S3). NM_000546.6:c.919+17A>G is a deep intronic variant (intron 8, +17) with no amino acid consequence (NP_000537.3:p.?) and no entry in the Functional worksheet, so none of the PS3 strength rules (non-functional or partially functional on Kato AND LOF by the majority of other eligible assays; non-functional on Kato AND abnormal on Kawaguchi) can be evaluated. No RNA- or protein-based functional assay data for this variant exists anywhere in the case bundle: the SpliceAI lookup returned no score, no minigene/RNA-seq assay data was collected, and none of the fetched full-text papers report variant-specific functional data. Per the VCEP v2.4 instructions-to-use caveat, splicing-related functional evidence for intronic variants is routed to PVS1_Variable Weight (RNA) or BP7, not PS3. PS3 is therefore not applicable to this variant.
Rule
PS3 (TP53 VCEP v2.4): Strong - Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays; Moderate - Partially functional on Kato et al. data AND LOF by the majority of other available assays; Supporting - Non-functional on Kato et al. data AND abnormal on Kawaguchi et al. data regardless of other assays (or small deletions demonstrating LOF on the majority of available assays).
Evidence considered
cspec: ClinGen TP53 VCEP specifications v2.4 define PS3_Strong as 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays', PS3_Moderate as 'Partially functional on Kato et al. data AND LOF by the majority of other available assays', and PS3_Supporting as 'Non-functional on Kato et al. data AND abnormal on Kawaguchi et al. data regardless of other assays' (plus small deletions with LOF on the majority of available assays); every pathway requires Kato et al. (PMID:12826609) transactivation data for the specific amino acid change, which cannot exist for an intronic variant with no protein consequence.
cspec: PS3 instructions-to-use state that functional missense codes are based on protein-level assays (Kato, Giacomelli) and add the caveat that if there is laboratory evidence of splicing aberration (including RNA-seq) the variant should be considered for PVS1_Variable Weight (RNA) instead, and functional missense codes should not be applied if PVS1 is applied for splicing - confirming splicing functional evidence is not assessed via PS3/BS3 in this VCEP.
vcep_flowchart_for_application_of_functional_rule_codes: The functional rule-codes flowchart applies PS3 and BS3 via protein function for missense variants (left branch) and small deletions (right branch) only; intronic variants are outside its scope.
vcep_functional_worksheet: The Functional worksheet (Supplementary Table S3) tabulates PS3/BS3 assignments for amino acid substitutions and deletions by amino acid change (e.g., Y126C); no row exists for c.919+17A>G / p.?, consistent with no functional assay data being applicable.
spliceai: The SpliceAI lookup for NM_000546.6:c.919+17A>G returned no score (search_status no_result), so no splicing-impact prediction is available for this deep intronic variant.
PMID:25741868: The ACMG/AMP 2015 guidelines state that confirmation of splice-site variant impact requires functional analysis by RNA or protein analysis and note mRNA-level assays can be informative for deeper intronic regions; this is generic methodology only and provides no variant-specific functional data for c.919+17A>G, so it cannot support PS3.
paper_extracts review: The three fetched full-text papers (PMID:25741868, PMID:20065170, PMID:26324357) were checked; none report any functional assay (protein- or RNA-based) for c.919+17A>G.
Still missing
No RNA-based functional splicing assay data (e.g., RNA-seq, minigene, RT-PCR) is available for c.919+17A>G; SpliceAI lookup returned no score for this deep intronic position, so functional relevance cannot be contextually anchored to a splicing prediction.
No protein-function assay data (Kato/Giacomelli/Kawaguchi/Kotler/Funk) exists for this variant because it does not alter an amino acid; the VCEP Functional worksheet has no row for p.?.
PM1N/ANot applicable: PM1 applies only to missense variants, and this intronic variant alters no codon (p.?).
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Reasoning
The TP53 VCEP v2.4 CSPEC PM1 rule applies only to missense variants: within codons 175, 245, 248, 249, 273, 282 (transcript NM_000546.4) at Moderate, or germline missense variants with 2-9 somatic occurrences in cancerhotspots.org at Supporting. c.919+17A>G is intronic (no codon is altered; protein p.?) and therefore cannot meet PM1. Per the domain-table instruction, vcep_materials.json's domain_tables key was checked and contains no entry for TP53 (empty object), so there was no authoritative VCEP domain table to evaluate the variant's residue against; the PM1 conclusion rests on the CSPEC rule text itself, which is restricted to missense variants.
Rule
TP53 VCEP v2.4 CSPEC PM1 (Moderate/Supporting) - missense variants only at hotspot codons 175/245/248/249/273/282 or with cancerhotspots.org somatic occurrences.
Evidence considered
TP53 VCEP v2.4 CSPEC PM1 rule (Moderate): missense variants within codons 175, 245, 248, 249, 273, 282 using transcript NM_000546.4, or germline missense variants with >=10 somatic occurrences in cancerhotspots.org; (Supporting): missense variants with 2-9 somatic occurrences in cancerhotspots.org.
vcep_materials.json domain_tables is {} for TP53 - no domain table entry exists, so no authoritative VCEP domain list was available to check.
VariantValidator classifies c.919+17A>G as intronic (positions 8i) with no protein consequence (p.?), so no amino acid residue is affected by this variant.
Still missing
vcep_materials.json domain_tables is empty for TP53; no approved VCEP critical functional domain table was available, so PM1 was assessed solely from the CSPEC PM1 rule text (missense-only).
No cancerhotspots.org somatic occurrence data were collected for this intronic variant (hotspots source data empty), but the rule only applies to germline missense variants.
PM3VCEPNot applicable: the TP53 VCEP excludes PM3, and Li-Fraumeni syndrome is autosomal dominant, not recessive.
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Reasoning
PM3 is not applicable under the governing TP53 VCEP v2.4 framework (ClinGen TP53 Expert Panel specifications, cspec.genome.network). The cspec marks PM3 as 'Not Applicable' and its code entry states: 'This rule does not apply to TP53/Li-Fraumeni syndrome.' Mechanistically this is consistent: PM3 requires a recessive disease model (variant detected in trans with a pathogenic variant, phase determined by parental/offspring testing), whereas TP53-associated Li-Fraumeni syndrome is inherited in an autosomal dominant manner. The variant c.919+17A>G is a deep intronic (+17) variant with no documented allelic (trans/cis) observations in the case evidence bundle, but this is moot given the framework exclusion. No generic ACMG fallback is needed because a governing VCEP specification exists and explicitly excludes this code.
Evidence considered
TP53 VCEP v2.4 cspec (cspec.genome.network) marks PM3 as 'Not Applicable'; the PM3 code entry states: 'This rule does not apply to TP53/Li-Fraumeni syndrome.'
Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome; PM3 (for recessive disorders, detected in trans with a pathogenic variant, phase requiring parental/offspring testing) is structurally inapplicable to a dominant disorder.
Case evidence bundle contains no phase-resolved observations of c.919+17A>G with a second TP53 variant (ClinVar VCV000378747 submissions carry no trans/cis phase data), but PM3 is excluded by the framework regardless.
PM4VCEPNot applicable: no in-frame insertion/deletion or stop-loss is produced; the protein is unchanged (p.?).
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Reasoning
PM4 (protein length change due to in-frame insertion/deletion or stop-loss) is declared Not Applicable by the governing TP53 VCEP CSPEC v2.4, which takes precedence over generic ACMG/AMP. Independently, the variant cannot meet PM4 on its merits: c.919+17A>G is intronic with a predicted protein consequence of p.? (no amino acid change, no protein length change, no stop-loss), so no in-frame indel or termination-codon loss is produced.
VCEP rule
TP53 VCEP CSPEC v2.4: PM4 Not Applicable.
Evidence considered
TP53 VCEP CSPEC v2.4 lists PM4 with applicability 'Not Applicable' - the criterion is not for use under this VCEP.
Variant normalization: NM_000546.6:c.919+17A>G maps to NP_000537.3:p.? (VariantValidator hgvs_predicted_protein_consequence), i.e. no protein-level consequence; PM4 requires a change in protein length, which cannot occur here.
PM5N/ANot applicable: PM5 requires a missense change at a residue with known pathogenic variants; this variant is intronic (p.?).
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Reasoning
The TP53 VCEP v2.4 CSPEC PM5 rule applies to novel missense changes at an amino acid residue where 1 or more different missense variants previously determined pathogenic (or likely pathogenic with clinical evidence) per the VCEP's specifications have been seen. c.919+17A>G is intronic with no missense consequence (p.?), so PM5 cannot apply. This is corroborated by pm5_candidates.json, which reports eligible_for_classic_pm5_search = false with recommendation level not_applicable because the variant consequence class is not missense, and 0 same-residue comparator candidates.
Rule
TP53 VCEP v2.4 CSPEC PM5 (Strong/Moderate/Supporting) - novel missense change at a residue with previously established pathogenic/likely pathogenic different missense variant(s).
Evidence considered
TP53 VCEP v2.4 CSPEC PM5 rule: missense variant at a residue where >=2 (Strong), 1 (Moderate) different pathogenic missense variants, or 1 likely pathogenic missense variant with clinical data demonstrating pathogenicity (Supporting) have been seen per the VCEP's specifications.
pm5_candidates.json: pm5_mode = classic_same_residue_missense, eligible_for_classic_pm5_search = false, recommendation = not_applicable ('the variant consequence class (unknown) is not missense'); 0 same-residue candidates seen.
Still missing
No same-residue missense comparator analysis is possible because the variant does not alter an amino acid residue.
PM6VCEPNot applicable: the TP53 VCEP has dropped PM6, using PS2 exclusively for all de novo evidence.
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Reasoning
PM6 is not applicable under the ClinGen TP53 VCEP v2.4 specifications (cspec): the VCEP has explicitly opted to drop PM6 and use PS2 exclusively for all de novo evidence. Any de novo observation of this variant would be adjudicated under the PS2 point system instead.
VCEP rule
Not applicable - TP53 VCEP v2.4 dropped PM6; de novo evidence is handled exclusively via PS2.
Evidence considered
ClinGen TP53 VCEP v2.4 (cspec) PM6 entry is marked Not applicable with instructions: 'See above for PS2_PM6 combined rule'; the PS2 instructions state 'To avoid redundancy and increase consistency, the TP53 VCEP has opted to drop PM6 and use PS2 exclusively for de novo evidence.'
PP2VCEPNot applicable: the TP53 VCEP excludes PP2, and the variant is intronic, not missense.
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Reasoning
The TP53 VCEP v2.4 CSPEC explicitly declares PP2 'Not Applicable' for TP53 (instructionsToUse: 'Not applicable'). Additionally, PP2 concerns missense variants in a gene with a low rate of benign missense variation and missense as a common disease mechanism, and c.919+17A>G is an intronic variant with no missense consequence. PP2 is therefore not applicable on both the gene-specification and variant-type grounds.
VCEP rule
TP53 VCEP v2.4 CSPEC PP2 - declared Not Applicable for TP53.
PP5VCEPNot applicable: no ClinVar expert-panel classification exists for this exact variant.
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Reasoning
PP5 is declared Not Applicable by the TP53 VCEP v2.4 ('This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee'). Under the global PP5/BP6 policy, PP5 may be applied at supporting strength only when an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic exists. ClinVar VCV000378747 contains 0 expert-panel submissions: its Likely benign label comes from 6 ordinary clinical laboratory submissions (GeneDx, Color Health, Genome-Nilou Lab x2, Labcorp/Invitae, Ambry), all 'criteria provided, single submitter'. No expert-panel assertion exists for this variant, so PP5 is not applicable and cannot be met.
VCEP rule
TP53 VCEP v2.4: PP5 Not Applicable. Global override: PP5 at supporting only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification.
Evidence considered
TP53 VCEP v2.4 (cspec) marks PP5 as 'Not Applicable for this VCEP' at all strengths.
ClinVar VCV000378747 (API review status 'criteria provided, multiple submitters, no conflicts', 2 stars): 6 submissions from 5 clinical laboratories, all classified Likely benign; submission audit reports expert_panel_submissions = 0 and usable_for_criterion_leads = 0.
Policy: PP5/BP6 are triggered only by an exact-variant ClinVar expert-panel classification; ordinary laboratory submissions and aggregate ClinVar labels must never trigger PP5 or BP6.
Full-text papers retrieved as PP5 candidates (PMID:20065170, PMID:26324357, PMID:25741868) do not mention c.919+17A>G and provide no reputable-source assertion for it.
Still missing
No ClinVar expert-panel (3-star) classification exists for c.919+17A>G that could trigger the PP5 override
BS3N/ANot applicable: BS3 requires functional assay data for the specific amino acid change, and none exists for this intronic variant.
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Reasoning
Under the governing ClinGen TP53 VCEP specification v2.4, BS3_Strong requires 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays' and BS3_Supporting requires 'Partially functional on Kato et al. data AND no evidence of LOF by all available assays' (or small deletions with available Kotler et al. data). Both pathways depend on Kato et al. (PMID:12826609) functional data for the specific amino acid change, which does not exist for NM_000546.6:c.919+17A>G because it is a deep intronic variant (intron 8, +17) with no protein consequence (p.?); the Functional worksheet has no entry for this variant. No functional assay evidence of any kind - protein-based or RNA-based - is present in the case bundle that could demonstrate a lack of damaging effect (no RNA-seq/minigene assay data, no SpliceAI score returned, no variant-specific functional data in any fetched full-text paper). Per the VCEP, RNA splicing evidence of no aberration for an intronic variant is handled through BP7_Strong (Walker et al. 2023, PMID:37352859) in the splicing group, not BS3. BS3 is therefore not applicable to this variant.
Rule
BS3 (TP53 VCEP v2.4): Strong - Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays; Supporting - Partially functional on Kato et al. data AND no evidence of LOF by all available assays (or small deletions with available Kotler et al. data that are LOF by the majority of available assays).
Evidence considered
cspec: ClinGen TP53 VCEP specifications v2.4 define BS3_Strong as 'Functional on Kato et al. data AND no loss of function (LOF) by the majority of available eligible assays' and BS3_Supporting as 'Partially functional on Kato et al. data AND no evidence of loss of function (LOF) by all available assays' (BS3_Supporting may also apply to small deletions with available Kotler et al. data that are LOF by the majority of available assays); all pathways require Kato et al. (PMID:12826609) data for the specific amino acid change, which does not exist for an intronic variant with no protein consequence.
cspec: BS3 instructions-to-use add the caveat that if there is any laboratory evidence of splicing aberration (including RNA-seq) for the variant, PVS1_Variable Weight (RNA) might be considered instead, and functional missense codes should not be applied if PVS1 is applied for splicing - i.e., splicing functional evidence for intronic variants is not adjudicated through BS3 in this VCEP.
vcep_flowchart_for_application_of_functional_rule_codes: The functional rule-codes flowchart applies PS3 and BS3 via protein function for missense variants (left branch) and small deletions (right branch) only; intronic variants are outside its scope.
vcep_functional_worksheet: The Functional worksheet (Supplementary Table S3) tabulates BS3 assignments by amino acid change; no row exists for c.919+17A>G / p.?, so no 'functional on Kato' determination can be made.
spliceai: The SpliceAI lookup for NM_000546.6:c.919+17A>G returned no score (search_status no_result), so no splicing-impact prediction is available to contextualize functional relevance.
PMID:25741868: The ACMG/AMP 2015 guidelines provide generic guidance that splice variant impact requires confirmation by RNA or protein functional analysis and that mRNA-level assays can inform deeper intronic variants; no variant-specific functional data is provided, so it cannot support BS3.
paper_extracts review: The three fetched full-text papers (PMID:25741868, PMID:20065170, PMID:26324357) were checked; none report any functional assay (protein- or RNA-based) for c.919+17A>G.
Still missing
No RNA-based functional assay demonstrating absence of splicing aberration (e.g., RNA-seq or minigene per Walker et al. 2023, PMID:37352859) is available for c.919+17A>G; such evidence would be evaluated under BP7_Strong in the splicing group, not BS3.
No Kato/Giacomelli/Kawaguchi/Kotler/Funk protein-function data exists for this variant because it has no amino acid substitution; the VCEP Functional worksheet has no row for p.?.
BP1VCEPNot applicable: the TP53 VCEP excludes BP1 because missense variants are a major disease mechanism in TP53.
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Reasoning
The TP53 VCEP v2.4 CSPEC explicitly declares BP1 'Not Applicable': 'This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.' TP53 (Li-Fraumeni syndrome) is a gene in which missense variants are a major disease mechanism, so the premise of BP1 (missense variant in a gene where primarily truncating variants cause disease) is false. The variant is also intronic rather than missense. BP1 is not applicable.
VCEP rule
TP53 VCEP v2.4 CSPEC BP1 - declared Not Applicable for TP53.
Evidence considered
TP53 VCEP v2.4 CSPEC lists BP1 applicability as 'Not applicable' with instructionsToUse: 'This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.'
Variant is intronic (c.919+17A>G, p.?) and is not a missense variant, so BP1's variant-type premise does not apply.
BP2VCEPNot applicable: the TP53 VCEP excludes BP2, and no trans/cis observation with a pathogenic variant is documented.
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Reasoning
BP2 is not applicable under the governing TP53 VCEP v2.4 framework: both the case_summary cspec parse and the full structured cspec record flag BP2 'Not Applicable' with every strength rule (Stand Alone through Supporting) marked not applicable. Note for the human reviewer: the full cspec record nevertheless carries a TP53-specific BP2 instructionsToUse text describing application scenarios (variant observed in trans with a pathogenic/likely pathogenic TP53 variant with phase confirmed; or 3+ observations with a pathogenic/likely pathogenic variant when phase is unknown, requiring at least two different P/LP TP53 variants) — this mirrors platform behavior where excluded codes retain their stored code text (the same pattern is seen for other Not-applicable codes such as BP1, BP3, PP5, BP6), and the structured applicability flags remain authoritative. Independently of applicability, the case bundle contains no evidence that would satisfy either BP2 scenario: ClinVar VCV000378747 (6 submissions, all Likely benign, germline, no conflicts) documents no phase-resolved trans/cis observation of c.919+17A>G with a pathogenic/likely pathogenic TP53 variant.
Evidence considered
TP53 VCEP v2.4 cspec marks BP2 'Not Applicable' (applicability flag 'Not applicable' with all strength rules not applicable) in both the case_summary cspec parse and the full structured cspec record, excluding BP2 from TP53 variant classification.
The cspec record's BP2 instructionsToUse text (variant in trans with a P/LP TP53 variant, phase confirmed; or >=3 observations with >=2 different P/LP TP53 variants when phase unknown) is stored code text carried on an otherwise Not-applicable code entry; applicability flags are treated as authoritative. Flagged for human confirmation.
ClinVar record VCV000378747 (6 submissions: GeneDx, Color, Genome-Nilou x2, Labcorp/Invitae, Ambry; all 'Likely benign', germline, review status 'criteria provided, multiple submitters, no conflicts') contains no phase-resolved (trans/cis) observations of c.919+17A>G with a pathogenic/likely pathogenic TP53 variant, so no allelic evidence would be available even if BP2 were applicable.
BP3VCEPNot applicable: no in-frame indel in a repetitive region; the variant is a single intronic substitution.
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Reasoning
BP3 is declared Not Applicable by the governing TP53 VCEP CSPEC v2.4, which takes precedence over generic ACMG/AMP. Independently, the generic ACMG/AMP 2015 BP3 (in-frame deletions/insertions in a repetitive region without a known function) does not apply: c.919+17A>G is an intronic single-nucleotide substitution (intron 8, +17) with no in-frame indel and no repeat-region context, so there is no repetitive-region in-frame change to evaluate.
VCEP rule
TP53 VCEP CSPEC v2.4: BP3 Not Applicable.
Evidence considered
TP53 VCEP CSPEC v2.4 lists BP3 with applicability 'Not Applicable' - the criterion is not for use under this VCEP.
Generic ACMG/AMP 2015 BP3 concerns in-frame indels in a repetitive region without known function; the variant here is an intronic substitution (c.919+17A>G, intron 8) producing no protein change (p.?) and is not located in a repetitive region, so the generic criterion is inapplicable even outside the VCEP.
BP5VCEPNot applicable: the TP53 VCEP excludes BP5, and no alternate molecular basis of disease is documented.
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Reasoning
BP5 (variant found in a case with an alternate molecular basis for disease) is declared Not Applicable by the TP53 VCEP v2.4. No data indicating an alternate molecular basis of disease in any carrier of c.919+17A>G is present in the case bundle, and the criterion is not for use under the governing framework. BP5 is therefore not applicable.
VCEP rule
TP53 VCEP v2.4: BP5 Not applicable.
Evidence considered
TP53 VCEP v2.4 (cspec) declares BP5 'Not applicable' for TP53.
BP6VCEPNot applicable: no ClinVar expert-panel benign classification exists; the Likely benign label comes only from routine laboratory submissions.
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Reasoning
BP6 is declared Not Applicable by the TP53 VCEP v2.4 ('not for use as recommended by the ClinGen SVI VCEP Review Committee'). Under the global PP5/BP6 policy, BP6 may be applied at supporting strength only when an exact-variant ClinVar expert-panel classification of Benign/Likely benign exists. Although ClinVar VCV000378747 carries an aggregate 'Likely benign' label, it derives solely from 6 ordinary clinical laboratory submissions (2-star review status, expert_panel_submissions = 0); ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6. BP6 is therefore not applicable.
VCEP rule
TP53 VCEP v2.4: BP6 Not Applicable. Global override: BP6 at supporting only for an exact-variant ClinVar expert-panel Benign/Likely benign classification.
Evidence considered
TP53 VCEP v2.4 (cspec) marks BP6 as 'Not Applicable for this VCEP' at all strengths.
ClinVar VCV000378747 aggregate label 'Likely benign' (2 stars) is based on 6 clinical-laboratory submissions; expert_panel_submissions = 0, so the label is not an expert-panel assertion and cannot trigger BP6.
Still missing
No ClinVar expert-panel (3-star) benign classification exists for c.919+17A>G that could trigger the BP6 override
AF 1.9e-06 · 3 / 1,614,156 alleles · 0 hom · FAF 2.8e-07
Remaining individuals1 / 62,506
1.6e-05
European (non-Finnish)2 / 1,180,044
1.7e-06
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85856e-06; MAF= 0.00019%, 3/1614156 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3Not assessed: no SpliceAI score was available to test the required >=0.2 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
NM_000546.6:c.919+17A>G is an intronic variant at the exon 8 donor +17 position, outside the +/-1,2 splice consensus positions. Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), the only applicable PP3 pathway for this variant type is the intronic splice variant rule: PP3 (supporting) requires a SpliceAI max delta score >= 0.2 for intronic variants excluding +/-1,2 positions. The missense BayesDel/aGVGD pathway does not apply because the variant has no protein consequence (p.?). The SpliceAI Lookup attempt in this case returned no score (evidence.json spliceai: search_status 'no_result', warning 'No SpliceAI score returned from API', scores empty, max_delta null), and neither the VCEP PP3-BP4-codes.xlsx (Supplementary Table S2, which covers only predicted missense variants) nor the PVS1-Splicing-Worksheet.xlsx (Table S1, which covers only +/-1,2 GT-AG variants) contains a pre-assigned PP3/BP4 code or SpliceAI score for c.919+17A>G (verified by direct read of both spreadsheets). Without a SpliceAI score, PP3 (>= 0.2) can be neither confirmed nor refuted, so the criterion is not assessed. A human reviewer should obtain the SpliceAI max delta score (e.g., re-run the SpliceAI Lookup or read the saved spliceai.png screenshot) before this code can be resolved.
Variant is intronic at exon 8 donor +17, so the missense BayesDel/aGVGD PP3 pathways (BayesDel >= 0.16 with aGVGD C25-C55 or C65) are not applicable; no protein consequence is predicted (p.?).
SpliceAI Lookup (source_registry key 'spliceai') returned no score for NM_000546.6:c.919+17A>G: evidence.json records search_status 'no_result' and warning 'No SpliceAI score returned from API'; case_summary spliceai block has empty scores and max_delta null.
Direct read of vcep_db/TP53/files/PP3-BP4-codes.xlsx (Supplementary Table S2, 2573 rows) found no entry containing 'c.919+17'; the table covers only predicted missense variants and notes SpliceAI must be considered separately.
Direct read of vcep_db/TP53/files/PVS1-Splicing-Worksheet.xlsx (Table S1, 1060 rows) found no entry for c.919+17A>G; the sheet covers GT-AG +/-1,2 splice site variants only.
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable (SpliceAI Lookup returned no result); PP3 supporting for intronic variants outside +/-1,2 requires SpliceAI >= 0.2.
No pre-assigned PP3/BP4 code for c.919+17A>G exists in the VCEP PP3-BP4-codes.xlsx or PVS1-Splicing-Worksheet.xlsx lookup tables.
BP4Not assessed: no SpliceAI score was available to test the required <=0.1 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), BP4 (supporting) for 'Silent or Intronic Variants (outside +/- 1,2 positions)' requires SpliceAI <= 0.1. c.919+17A>G is an intronic variant at +17 (outside +/-1,2), so this is the only applicable BP4 pathway; the missense BayesDel pathways (BP4_Moderate: BayesDel <= -0.008; BP4: BayesDel < 0.16 and > -0.008, both with SpliceAI < 0.2) do not apply to an intronic variant with no protein consequence. The SpliceAI score is unavailable in this case (SpliceAI Lookup returned no result; warning 'No SpliceAI score returned from API'), and the VCEP lookup spreadsheets contain no pre-assigned entry for c.919+17A>G. Because SpliceAI <= 0.1 can be neither confirmed nor refuted, BP4 is not assessed. Human review is needed to obtain the SpliceAI score before applying BP4.
Rule
Silent or intronic variants (outside +/-1,2 positions): BP4 (supporting) if SpliceAI <= 0.1 (ClinGen TP53 VCEP Specifications v2.4).
Variant is intronic at +17 with no predicted protein consequence, so the missense BayesDel BP4 pathways are not applicable.
SpliceAI Lookup (source_registry key 'spliceai') returned no score: evidence.json records search_status 'no_result' and warning 'No SpliceAI score returned from API'; case_summary spliceai block has empty scores and max_delta null.
Direct read of vcep_db/TP53/files/PP3-BP4-codes.xlsx found no entry for c.919+17A>G (table covers predicted missense variants only).
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable; BP4 supporting for intronic variants outside +/-1,2 requires SpliceAI <= 0.1.
No pre-assigned BP4 code for c.919+17A>G exists in the VCEP PP3-BP4-codes.xlsx lookup table.
BP7Not assessed: no SpliceAI score to confirm the <=0.1 requirement, and no RNA assay data are available. Flagged for human review: the SpliceAI score has not yet been obtained.
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Reasoning
Under the governing ClinGen TP53 VCEP v2.4 specifications (cspec), BP7 (supporting) applies to 'an intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI <= 0.1)'. c.919+17A>G is at +17, satisfying the positional requirement, and no nucleotide-conservation assessment is required per the VCEP rule (per Walker et al. 2023, PMID 37352859 as cited in the rule). However, the SpliceAI score is unavailable (SpliceAI Lookup returned no result; warning 'No SpliceAI score returned from API'), so the SpliceAI <= 0.1 requirement cannot be confirmed. The stronger BP7_Strong pathway requires RNA splicing assay data demonstrating no splicing aberration; no RNA assay data for this variant is present in the case evidence bundle, so BP7_Strong is not met. BP7 is therefore not assessed pending retrieval of the SpliceAI score.
Rule
BP7 (supporting): intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor creation of a new splice site (BP4 met, SpliceAI <= 0.1); BP7_Strong: RNA splicing assay data demonstrates no splicing aberration (ClinGen TP53 VCEP Specifications v2.4).
Evidence considered
TP53 VCEP v2.4 BP7 rule (supporting): intronic variant at or beyond +7 to -21 positions with SpliceAI predicting no impact (SpliceAI <= 0.1, i.e., BP4 met); no conservation assessment required per Walker et al. 2023 (PMID 37352859) as cited in the rule.
Variant position: intronic +17 relative to exon 8 donor, which is within the '+7 to -21' window, satisfying the positional component of BP7 supporting.
SpliceAI Lookup (source_registry key 'spliceai') returned no score for NM_000546.6:c.919+17A>G (evidence.json search_status 'no_result', warning 'No SpliceAI score returned from API').
BP7_Strong requires RNA splicing assay data demonstrating no splicing aberration; no RNA-based assay data for this variant was found in the case evidence bundle (evidence.json, literature_pass.json, paper_extracts.json reviewed).
Still missing
SpliceAI max delta score for NM_000546.6:c.919+17A>G is unavailable; BP7 supporting requires SpliceAI <= 0.1 (BP4 met).
No RNA splicing assay data is available for this variant, so the BP7_Strong pathway (RNA assay demonstrates no splicing aberration, per Walker et al. 2023, PMID 37352859 as cited in the VCEP rule) cannot be evaluated.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The paper does not mention TP53 c.919+17A>G or assign a protein consequence. In general, it states that intronic splice-site variants may affect RNA processing through exon skipping, exon shortening, intronic sequence inclusion, alternative splice-site usage, or creation of new splice sites, and that the impact of such variants should be confirmed with RNA- or protein-based functional analysis. It also notes that mRNA-level assays can be informative for variants in deeper intronic regions.
For splice site variants, the variant may lead to exon skipping, shortening or inclusion of intronic material, due to alternative donor/acceptor site usage or creation of new sites. Although splice site variants are predicted to lead to a null effect, confirmation of impact requires functional analysis by either RNA or protein analysis.
Proposed Criteria for Interpretation of Sequence Variants, PVS1 Null variants
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
Robson ME et al. · 2010
ASCO policy statement on genetic and genomic testing for cancer susceptibility (clinical utility, counseling, consent, access, privacy, regulation). It reports no TP53-specific or variant-specific data; no functional assay, case observation, segregation, or population-frequency information relevant to c.919+17A>G or to any residue/domain criterion is provided.
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
ASCO policy statement update on genetic and genomic testing for cancer susceptibility. It mentions TP53 only as an example of a gene where multigene panel testing may reveal an unexpected Li-Fraumeni syndrome mutation; it does not report c.919+17A>G or any variant-specific residue/domain data.
Some unexpected results, such as a mutation in TP53 (Li-Fraumeni syndrome) or CDH1 (hereditary diffuse gastric cancer), may have a significant impact on the patient and his or her family, so it is important that the patient is prepared for this possibility.
Multigene Panel Testing for Cancer Susceptibility, paragraph following Table 1
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85856e-06; MAF= 0.00019%, 3/1614156 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories). (ClinVarID = 378747)
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).
This variant was interpreted by pipeline 7.1.5.
The current version is 11.0.07.
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