TP53 c.797G>T, p.(Gly266Val)

Reasoning

TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) contains an exact amino-acid-change match for G266V: Kato et al. transactivation class = Non-functional, and the other eligible systematic assays (Giacomelli 2018 growth-suppression, Kotler 2018 fitness, and related columns) are concordantly LOF/LOF/LOF, with the worksheet's own pre-assigned code listed as 'PS3'. This satisfies the TP53 VCEP PS3 Strong rule: 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays.' The VCEP caveat that functional missense codes (PS3/BS3) should not be applied if PP3 is triggered by SpliceAI does not apply here: SpliceAI predicts no meaningful splicing impact for this variant (max delta score 0.17, below the VCEP's 0.2 PP3 threshold), so there is no splicing-based conflict precluding protein-level functional evidence.

Rule

TP53 VCEP PS3 Strong: Non-functional on Kato et al. data AND LOF by majority of other eligible assays

Evidence considered

• VCEP Functional-worksheet.xlsx (Supplementary Table S3) exact match row for G266V: Kato = Non-functional, other assay columns = LOF/LOF/LOF, worksheet-assigned code = PS3.
• TP53 VCEP PS3 rule (cspec v2.4): 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays' = PS3 Strong.
• TP53 VCEP eligible functional assays per Flowchart-for-application-of-functional-rule-codes.pdf: Kato (PMID:12826609), Funk (PMID:39774325), Giacomelli (PMID:30224644), Kotler (PMID:29979965), Kawaguchi (PMID:16007150).
• SpliceAI lookup for NM_000546.6:c.797G>T shows max delta score 0.17 (DS_AG 0.17, DS_AL 0.111, DS_DG 0.002, DS_DL 0.001), below the TP53 VCEP PP3 SpliceAI threshold of 0.2, so the VCEP caveat against applying protein-level PS3/BS3 when PP3 is met via SpliceAI does not apply.

Still missing

• The underlying source papers for the individual assay calls (Kato PMID:12826609, Giacomelli PMID:30224644, Kotler PMID:29979965) do not explicitly name p.G266V/c.797G>T in their available full text per paper_extracts.json; the variant-level functional call is sourced from the VCEP's own curated Functional-worksheet.xlsx aggregate table (Supplementary Table S3), not from a directly quotable sentence in the primary literature.
• Individual per-assay quantitative values (e.g., Kato transactivation % activity, Giacomelli etoposide Z-score, Kotler RFS) were not independently retrieved beyond the worksheet's categorical LOF/non-functional calls.

Sources

Reasoning

PM2_supporting is met under the TP53 VCEP v2.4 rule. NM_000546.6:c.797G>T is absent from gnomAD v4.1 and gnomAD-Canada v1.0 and has gnomAD v2.1 total AF 0 (0/248,882 alleles) with 0 homozygotes. The frequency is below 0.00003, and no ancestry group has multiple observed alleles requiring the <0.00004 subgroup check. The TP53 VCEP specifies that PM2 is applied at supporting strength.

Rule

TP53 VCEP v2.4: apply PM2 at supporting strength when total AF is <0.00003; if multiple alleles are present in an ancestry group, that group must have AF <0.00004; ignore founder-effect groups.

Evidence considered

• The governing ClinGen TP53 VCEP specification, version 2.4, requires PM2_supporting for AF <0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group must have AF <0.00004, and founder-effect groups are ignored.
• gnomAD v2.1 reports 0 variant alleles among 248,882 tested alleles, total AF 0, and 0 homozygotes; every listed ancestry group has 0 observed variant alleles.
• The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

BA1 is not met. The TP53 VCEP v2.4 stand-alone benign threshold is FAF >=0.001 in an eligible continental ancestry group with >=2,000 alleles tested and at least 2 variant alleles. NM_000546.6:c.797G>T is absent from gnomAD v4.1 and gnomAD-Canada; gnomAD v2.1 reports 0/248,882 alleles overall and 0/16,110 African/African American alleles, with no homozygotes. The observed frequency is therefore below the BA1 threshold.

Rule

TP53 VCEP v2.4: BA1 stand-alone when eligible continental-subpopulation FAF is >=0.001, with >=2,000 alleles tested and >=2 variant alleles; founder-effect groups are excluded.

Evidence considered

• The governing ClinGen TP53 VCEP specification, version 2.4, defines BA1 as FAF >=0.001 in an eligible continental subpopulation, requiring at least 2,000 alleles tested and at least 2 variant alleles.
• gnomAD v2.1 reports total allele count 0 of 248,882, total AF 0, and 0 homozygotes; the highest reported ancestry-group count is African/African American with 0 of 16,110 alleles and 0 homozygotes.
• The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

BS1 is not met. The TP53 VCEP v2.4 strong benign threshold is FAF >=0.0003 and <0.001 in an eligible continental ancestry group with >=2,000 alleles tested and at least 2 variant alleles. NM_000546.6:c.797G>T is absent from gnomAD v4.1 and gnomAD-Canada; gnomAD v2.1 shows no observed variant alleles or homozygotes overall or in the reported ancestry groups, so the frequency does not reach the BS1 range.

Rule

TP53 VCEP v2.4: BS1 strong when eligible continental-subpopulation FAF is >=0.0003 and <0.001, with >=2,000 alleles tested and >=2 variant alleles; founder-effect groups are excluded.

Evidence considered

• The governing ClinGen TP53 VCEP specification, version 2.4, defines BS1 strong when eligible continental-subpopulation FAF is >=0.0003 but <0.001, with >=2,000 alleles tested and at least 2 variant alleles; founder-effect groups are excluded and low allele balance requires caution.
• gnomAD v2.1 reports 0/248,882 alleles overall, AF 0, and 0 homozygotes; the reported African/African American group has 0/16,110 alleles and AF 0.
• The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

The TP53 VCEP Functional-worksheet.xlsx shows a concordant loss-of-function functional profile for G266V (Kato Non-functional; other eligible assays LOF), which is the mirror-image opposite of the BS3 requirement ('Functional on Kato et al. data AND no LOF by the majority of available eligible assays' for Strong, or 'Partially functional on Kato et al. data AND no evidence of LOF by all available assays' for Supporting). No functional evidence in the reviewed materials supports a benign/no-damaging-effect interpretation for this variant.

Rule

TP53 VCEP BS3: requires functional or partially-functional Kato data with no LOF by other assays; not met for G266V

Evidence considered

• VCEP Functional-worksheet.xlsx exact match row for G266V shows Non-functional/LOF across assays, which is inconsistent with either BS3 Strong or Supporting rule (both require functional/no-LOF or partially-functional/no-LOF results).

Sources

Reasoning

TP53 VCEP cspec v2.4 BP4 missense rule requires BayesDel <=-0.008 (Moderate) or BayesDel <0.16 and >-0.008 (Supporting), irrespective of aGVGD (except aGVGD C65, which blocks BP4), AND no predicted splicing difference (SpliceAI <0.2). The local BayesDel score for NM_000546.6:c.797G>T (p.Gly266Val) is 0.599005, which is well above both the Moderate and Supporting benign thresholds, so BP4 cannot be met via the BayesDel pathway regardless of the (unretrieved) aGVGD class. SpliceAI max delta score is 0.17 (<0.2), satisfying only the ancillary 'no predicted splicing difference' clause, which cannot offset the disqualifying BayesDel score. The VCEP's own PP3-BP4-codes.xlsx spreadsheet did not return an exact-match row for this variant, so no VCEP pre-assigned override applies. BP4's synonymous/intronic SpliceAI<=0.1 pathway does not apply since this is a missense variant.

Rule

TP53 VCEP (cspec v2.4) BP4, missense pathway: BayesDel <=-0.008 (irrespective of aGVGD except C65) => BP4_Moderate; BayesDel <0.16 and >-0.008 (irrespective of aGVGD except C65) => BP4_Supporting; both require SpliceAI <0.2.

Evidence considered

• TP53 VCEP cspec v2.4 BP4 rule (missense): BayesDel <=-0.008 irrespective of aGVGD (except C65) => BP4_Moderate; BayesDel <0.16 and >-0.008 irrespective of aGVGD (except C65) => BP4_Supporting; AND no predicted splicing difference (SpliceAI <0.2).
• Local BayesDel predictor lookup (BayesDel_170824_noAF, chr17) score = 0.599005 for NM_000546.6:c.797G>T, exceeding both BP4 benign thresholds, ruling out BP4 regardless of aGVGD class.
• SpliceAI Lookup: max delta score = 0.17 (<0.2), satisfying the 'no predicted splicing difference' clause, but insufficient alone to meet BP4 given the disqualifying BayesDel score.
• vcep_pp3_bp4_codes (PP3-BP4-codes.xlsx, Supplementary Table S2) preview did not include an exact-match row for c.797G>T / p.Gly266Val.

Sources

Reasoning

PS1 (TP53 VCEP) requires that a different nucleotide change resulting in the same amino acid change, p.(Gly266Val), has already been classified Pathogenic/Likely Pathogenic per the TP53 VCEP's own specifications. No comparator variant data (alternate codon changes producing the identical p.G266V substitution with an established VCEP classification) was retrieved in this case bundle. ClinVar record 233303 pertains to this exact variant itself (conflicting Uncertain significance/Pathogenic submissions) and cannot be used as a same-amino-acid-change comparator for PS1.

Rule

TP53 VCEP CSpec v2.4 PS1

Evidence considered

• TP53 VCEP CSpec v2.4 PS1 rule: Strong if variant asserted Pathogenic per TP53 VCEP specifications; Moderate if asserted Likely Pathogenic per TP53 VCEP specifications.
• No alternate-codon-change comparator data for p.(Gly266Val) was captured in prefetch/evidence/pm5_candidates artifacts for this case.

Still missing

• No search was performed/retrieved for alternate nucleotide changes at codon 266 encoding the same p.G266V substitution with a prior VCEP-based pathogenic/likely pathogenic classification.

Sources

Reasoning

The TP53 VCEP specifies PS2 for de novo evidence, with points tallied across probands according to confirmation of maternity and paternity and the proband's LFS-associated cancer. The case-evidence bundle contains no proband clinical phenotype, parental testing results, maternity/paternity confirmation, or documented de novo observation for NM_000546.6:c.797G>T (p.Gly266Val).

Rule

TP53 VCEP Version 2.4: de novo points are tallied using the proband-point table according to confirmed maternity and paternity and the type of cancer in the proband; PS2 is supporting at 1 point, moderate at 2-3 points, strong at 4-7 points, and very strong at >=8 points.

Evidence considered

• The TP53 VCEP Version 2.4 rule states that de novo points are tallied using proband cancer type and whether maternity and paternity are confirmed, with PS2 strength thresholds of supporting for 1 point, moderate for 2-3 points, strong for 4-7 points, and very strong for at least 8 points.
• The consolidated case-evidence bundle provides no case-specific parental testing, maternity/paternity confirmation, proband cancer phenotype, or confirmed de novo documentation for this variant.

Still missing

• Documented proband LFS-associated cancer phenotype and age at diagnosis
• Parental genotypes and explicit confirmation of maternity and paternity
• Evidence that the variant is absent from both parents or otherwise confirmed de novo
• Any additional confirmed de novo probands and their applicable VCEP point assignments

Sources

Reasoning

The TP53 VCEP PS4 point-based framework applies, but the bundle contains no eligible independent germline proband observations with Li-Fraumeni syndrome-associated cancer diagnoses from which PS4 points can be assigned.

Rule

TP53 VCEP PS4: assign strength from accumulated eligible Li-Fraumeni syndrome cancer points; Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, Very Strong at least 8.

Evidence considered

• TP53 VCEP version 2.4 specifies PS4 point thresholds: Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong at least 8 points.
• No exact-variant case series, case-control comparison, or individual germline cancer phenotype data are present in the consolidated bundle.

Still missing

• Variant-specific, non-duplicated germline proband data with cancer type, age at diagnosis, and sufficient detail to assign TP53 VCEP PS4 points are required.

Sources

Reasoning

Codon 266 is not among the six codons (175, 245, 248, 249, 273, 282) explicitly listed for TP53 VCEP PM1_Moderate application; this is corroborated by literature stating the well-known TP53 hotspot codons are 175, 220, 245, 248, 273 and 282 (codon 266 absent from that list). The VCEP rule also allows PM1 via cancerhotspots.org with quantitative somatic occurrence thresholds (>=10 = Moderate, 2-9 = Supporting). The case evidence includes a cancerhotspots.org lookup that flags G266 as lying in 'a statistically significant hotspot,' but the scrape explicitly warns the result was a partial regex extraction with no verified occurrence count, and no source_registry key exists for cancerhotspots.org or COSMIC to formally cite this data. A COSMIC record (COSV52666760) separately shows 110 somatic reports of the exact amino-acid change, but COSMIC is a distinct database from cancerhotspots.org and is not itself named in the VCEP rule, and it too lacks a source_registry key.

Rule

TP53 VCEP CSpec v2.4 PM1

Evidence considered

• TP53 VCEP CSpec v2.4 PM1 rule: Moderate for missense variants at codons 175, 245, 248, 249, 273, 282 (NM_000546.4) or for germline missense variants seen in cancerhotspots.org with >=10 somatic occurrences of the same amino acid change; Supporting for 2-9 somatic occurrences.
• PMID:27328919 states: 'The well-known hotspots for single base substitutions include codons 175, 220, 245, 248, 273 and 282, where missense mutations affect either the 3D structure of the p53 protein or its contact with DNA and result in loss of function' -- codon 266 is not included in this hotspot list, and the paper provides no variant-specific data on p.G266V.
• cancerhotspots.org lookup (evidence.json, no source_registry key) returned 'This variant lies in a statistically significant hotspot' but flagged the extraction as partial/unverified with no numeric occurrence count captured.
• COSMIC lookup (evidence.json, no source_registry key) reports 110 somatic occurrences of the identical amino acid change (COSV52666760), which is suggestive but is a different database than the one named in the VCEP rule and cannot substitute for a verified cancerhotspots.org count.

Still missing

• Exact cancerhotspots.org somatic occurrence count for G266 substitutions needs verification (only a qualitative 'statistically significant hotspot' flag was captured, with an explicit partial-extraction warning; the underlying screenshot was not independently confirmed).
• No source_registry entry exists for cancerhotspots.org or COSMIC, so this evidence cannot be formally cited without a registered source key.

Sources

Reasoning

PM5 (TP53 VCEP) requires a different missense variant at the same residue (codon 266) already determined Pathogenic (Strong: >=2 such variants) or Likely Pathogenic (Moderate: 1 such variant; Supporting tier requires additional PS2/PS4/PP1-level clinical data) per the TP53 VCEP's own specifications. The dedicated pm5_candidates.json artifact explicitly reports a failed same-residue comparator search (HTTP 429 rate limiting), zero same-residue candidates retrieved, and instructs that PM5 should not be applied from this artifact alone. The TP53 functional worksheet lists G266A (BS3_Supporting) and G266C (PS3_Supporting) at the same residue, but these are functional-assay-derived codes, not VCEP clinical pathogenicity classifications, so they cannot establish the 'previously determined pathogenic/likely pathogenic' comparator PM5 requires.

Rule

TP53 VCEP CSpec v2.4 PM5

Evidence considered

• TP53 VCEP CSpec v2.4 PM5 rule: Strong if >=2 other missense variants at the same residue are VCEP-pathogenic; Moderate if 1 other missense variant at the residue is VCEP-likely-pathogenic; Supporting tier requires the likely-pathogenic comparator to also carry PS2/PS4/PP1-level clinical data.
• pm5_candidates.json: same-residue comparator search returned found=false, same_residue_candidates=0, with error 'HTTP Error 429: Too Many Requests', and explicit instruction not to apply PM5 from this artifact alone.
• VCEP Functional-worksheet.xlsx (Supplementary Table S3) lists G266A as Partially functional/BS3_Supporting and G266C as AASub(no Kato data)/LOF/PS3_Supporting -- functional-assay codes only, not clinical pathogenicity classifications, so insufficient for PM5.

Still missing

• Same-residue (codon 266) ClinVar comparator search failed with HTTP 429 (rate limited) per pm5_candidates.json; needs to be re-run to identify any other missense variants at codon 266 with an established TP53 VCEP pathogenic/likely pathogenic classification.
• Functional worksheet entries for G266A/G266C are functional-assay codes (BS3_Supporting/PS3_Supporting), not VCEP clinical classifications, and cannot be used to satisfy PM5 without independent clinical classification data.

Sources

Reasoning

The TP53 VCEP requires cosegregation to be counted as meioses in individuals who carry the variant and have a relevant LFS-associated cancer, with unaffected obligate carriers also eligible for meiosis counting. The case-evidence bundle contains no family pedigree, affected relatives, carrier results, tumor/germline phase information, or countable meioses.

Rule

TP53 VCEP Version 2.4: cosegregation is supporting for 3-4 meioses, moderate for 5-6 meioses, and strong for >=7 meioses across >1 family; relevant cancers and variant carriage must be documented.

Evidence considered

• The TP53 VCEP Version 2.4 PP1 rule counts meioses for individuals who both carry the variant and have a relevant cancer, and permits counting through unaffected obligate carriers.
• The VCEP PP1 thresholds are supporting for 3-4 cosegregating meioses, moderate for 5-6 meioses, and strong for at least 7 meioses across more than one family.
• The consolidated case-evidence bundle contains no family segregation observations or other countable meioses for this variant.

Still missing

• Family pedigree and relationships
• Variant testing results for affected and unaffected relatives
• LFS-associated cancer diagnoses and ages for relatives
• A documented meiosis count and whether observations are from one or multiple families

Sources

Reasoning

NM_000546.6:c.797G>T (NP_000537.3:p.(Gly266Val)) is a missense variant. Per TP53 VCEP cspec v2.4, missense PP3 requires BOTH an aGVGD class AND a BayesDel score >=0.16 (aGVGD Class C65 -> PP3_Moderate; aGVGD C25-C55 -> PP3_Supporting), with tool selection justified by Fortuno et al. 2018's comparison of bioinformatic predictors for TP53. The local BayesDel lookup gives a score of 0.599005 for this variant, well above the 0.16 floor, but no aGVGD class was retrieved anywhere in this case's evidence collection (no aGVGD screenshot/lookup was performed, and the gene_vcep_files/screenshots inventories contain no aGVGD source). The VCEP's own pre-computed PP3-BP4-codes.xlsx spreadsheet, which pairs aGVGD class with BayesDel score per variant, did not return an exact-match row for c.797G>T in the materials extracted for this case (unlike Functional-worksheet.xlsx, which did return an exact G266V match for PS3/BS3). The alternate splice-effect PP3 pathway for apparent missense variants (SpliceAI >=0.2) is also not met: SpliceAI max delta score = 0.17 (<0.2). Because a required paired input (aGVGD) is missing and the VCEP spreadsheet lookup did not resolve this specific variant, PP3 strength cannot be confidently assigned at either Moderate or Supporting despite the qualifying BayesDel score.

Rule

TP53 VCEP (cspec v2.4) PP3, missense pathway: aGVGD Class C65 AND BayesDel >=0.16 => PP3_Moderate; aGVGD Class C25-C55 AND BayesDel >=0.16 => PP3_Supporting.

Evidence considered

• TP53 VCEP cspec v2.4 PP3 rule (missense): aGVGD Class C65 AND BayesDel >=0.16 -> PP3_Moderate; aGVGD Class C25-C55 AND BayesDel >=0.16 -> PP3_Supporting; instructionsToUse cites Fortuno et al. 2018 (PMID: 29775997) for selection of aGVGD and BayesDel as the TP53-calibrated missense predictors.
• Local BayesDel predictor lookup (BayesDel_170824_noAF, chr17) score = 0.599005 for NM_000546.6:c.797G>T, exceeding the 0.16 qualifying threshold, but strength cannot be set without the paired aGVGD class.
• SpliceAI Lookup: max delta score = 0.17 (DS_AG=0.17, DS_AL=0.111, DS_DG=0.002, DS_DL=0.001), below the VCEP's 0.2 threshold for the exonic/splice-effect PP3 pathway, so that alternate route to PP3 is also not triggered.
• vcep_pp3_bp4_codes (PP3-BP4-codes.xlsx, Supplementary Table S2) preview extracted for this case shows only unrelated example rows (c.266C>T/G/A, p.Pro89Leu/Arg/His); no row matching c.797G>T / p.Gly266Val was surfaced, unlike the Functional-worksheet.xlsx lookup which did return an exact G266V match for PS3/BS3.

Still missing

• aGVGD class not retrieved for NM_000546.6:c.797G>T (p.Gly266Val); required alongside BayesDel score per TP53 VCEP missense PP3 rule to distinguish PP3_Moderate vs PP3_Supporting
• PP3-BP4-codes.xlsx VCEP spreadsheet lookup (Supplementary Table S2) did not return an exact-match row for this coding change in the materials available to this review

Sources

Reasoning

The TP53 VCEP PP4 rule requires eligible observations of this variant with a specified variant allele fraction (VAF). No such observation or VAF data are supplied.

Rule

TP53 VCEP PP4: Moderate for at least 2 independent observations with VAF 5-25%; Supporting for observation(s) with VAF 5-35% as specified.

Evidence considered

• TP53 VCEP version 2.4 permits PP4_Moderate for at least two independent observations with VAF 5-25%, and PP4_Supporting for an observation with VAF 5-35% under its stated conditions.
• The consolidated bundle contains no VAF-bearing observations for NM_000546.6:c.797G>T (p.Gly266Val).

Still missing

• At least one eligible observation with VAF 5-35% is required for PP4_Supporting; two independent observations each with VAF 5-25% are required for PP4_Moderate.

Sources

Reasoning

ClinVar contains no exact-variant expert-panel Pathogenic or Likely pathogenic assertion. The available Pathogenic assertion is from a single clinical laboratory and cannot support PP5.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• ClinVar variation 233303 has conflicting classifications and one review star; its submissions include one Pathogenic single-submitter laboratory assertion and no expert-panel submissions.
• Ordinary laboratory assertions and aggregate ClinVar labels were not used for PP5.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is required.

Sources

Reasoning

BS2 cannot be assessed from the available case bundle. The TP53 VCEP requires unrelated female carriers from a single source who reached at least age 60 without cancer: 2-3 for supporting, 4-7 for moderate, or >=8 for strong. No carrier-level age, sex, cancer-status, source, or VAF data are provided. Population absence and zero homozygote counts do not establish BS2.

Rule

TP53 VCEP v2.4: BS2 supporting for 2-3, moderate for 4-7, or strong for >=8 unrelated female carriers from one source who reached at least age 60 without cancer; exclude qualifying sarcoma and likely somatic low-VAF observations.

Evidence considered

• The governing ClinGen TP53 VCEP specification, version 2.4, requires 2-3, 4-7, or >=8 unrelated female carriers from a single source who reached at least age 60 without cancer for BS2 supporting, moderate, or strong, respectively; individuals with sarcoma diagnosed at age >=61 are excluded and VAF <=35% suggests somatic origin.
• The case bundle contains no qualifying healthy-carrier series or individual-level BS2 data.

Still missing

• Carrier-level data from one source identifying unrelated females with the variant who reached at least age 60 without cancer, including sex, age, cancer status, source provenance, and VAF where available.

Sources

Reasoning

The TP53 VCEP defines BS4 as lack of segregation in affected family members with LFS-associated cancers. The case-evidence bundle contains no affected relatives who tested negative for the variant and no documented non-segregation analysis; therefore BS4 cannot be applied or rejected from the available evidence.

Rule

TP53 VCEP Version 2.4: BS4 supporting evidence is not applicable; strong BS4 may be applied for lack of segregation in affected family members with LFS-associated cancers, accounting for phenocopies and alternative pathogenic variants.

Evidence considered

• The TP53 VCEP Version 2.4 BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers.
• The VCEP cautions that phenocopies and more than one pathogenic variant in a family can mimic lack of segregation.
• The consolidated case-evidence bundle contains no affected non-carriers or other case-specific non-segregation evidence for this variant.

Still missing

• Affected family members with LFS-associated cancers
• Reliable variant testing results for those affected relatives
• Assessment of possible phenocopies or an alternative pathogenic variant in the family

Sources

Reasoning

ClinVar contains no exact-variant expert-panel Benign or Likely benign assertion. The available non-expert submissions cannot support BP6.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• ClinVar variation 233303 has conflicting classifications and one review star; no expert-panel submission is present.
• Ordinary laboratory assertions and aggregate ClinVar labels were not used for BP6.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign classification is required.

Sources