TP53 c.587G>T, p.(Arg196Leu)

Rule

TP53 PM2 is applied only at Supporting strength for variants with allele frequency <0.00003 overall and <0.00004 in any non-founder ancestry group when multiple alleles are present.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• TP53 VCEP PM2 threshold <0.00003 overall AF

Sources

Rule

TP53 PP3_Moderate for missense variants requires aGVGD Class C65 and BayesDel >=0.16.

Evidence considered

• PP3-BP4 row: c.587G>T
• p.Arg196Leu
• Class C65
• BayesDel 0.583489
• PP3_moderate
• SpliceAI 0.14
• REVEL score 0.933
• SpliceAI max delta 0.14

Sources

Rule

TP53 BS3_Supporting applies when Kato data are partially functional and all available eligible assays show no loss of function.

Evidence considered

• Functional worksheet row: R196L
• Kato result: partially functional
• other eligible assays: noLOF
• noLOF
• worksheet assignment: BS3_Supporting

Sources

Rule

TP53 PS3 requires non-functional or partially functional Kato results together with loss of function across the majority of other eligible assays.

Evidence considered

• Functional worksheet row: R196L
• Kato result: partially functional
• other eligible assays: noLOF
• noLOF
• worksheet assignment: BS3_Supporting

Sources

Rule

TP53 PM1 applies to specific hotspot codons or to Cancer Hotspots exact amino acid changes with 2-9 occurrences at Supporting or >=10 occurrences at Moderate strength.

Evidence considered

• TP53 predefined hotspot codons are 175
• 245
• 248
• 249
• 273
• and 282
• COSMIC somatic count = 3
• hotspot parse was uncertain

Still missing

• Cancer Hotspots exact-variant recurrence at p.Arg196Leu was not independently confirmed.

Sources

Rule

TP53 BA1 requires filtering allele frequency >=0.001 in an eligible non-founder ancestry group.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• BA1 threshold >=0.001

Sources

Rule

TP53 BS1 requires filtering allele frequency >=0.0003 and <0.001 in an eligible non-founder ancestry group.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• BS1 threshold >=0.0003

Sources

Rule

TP53 BP4 for missense variants requires BayesDel below the PP3 threshold range together with no predicted splicing impact.

Evidence considered

• PP3-BP4 row assigns PP3_moderate
• BayesDel 0.583489
• SpliceAI max delta 0.14

Sources

Rule

Can be applied when the same amino acid change has already been established as pathogenic or likely pathogenic under TP53 VCEP specifications.

Evidence considered

• available ClinVar record reviewed
• TP53 VCEP requires same amino acid change as an established pathogenic or likely pathogenic variant

Still missing

• No verified same-amino-acid TP53 VCEP comparator was identified.

Sources

Rule

TP53 PS2 is point-based: Supporting 1 point, Moderate 2-3 points, Strong 4-7 points, Very Strong >=8 points.

Evidence considered

• ClinVar record reviewed for case-level comments
• TP53 VCEP de novo scoring requires proband point assignment

Still missing

• No maternity/paternity-confirmed de novo report was identified.
• No proband cancer-point data were available for PS2 scoring.

Sources

Rule

TP53 PS4 is point-based after rarity is established: Supporting 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, Very Strong >=8 points.

Evidence considered

• variant is absent from gnomAD
• ClinVar lists VUS submissions but no scored TP53 proband framework evidence

Still missing

• No TP53 proband point total was available.
• No case-control enrichment or counted proband series was identified.

Sources

Rule

TP53 PM5 uses classic same-residue missense logic: 1 pathogenic comparator = Moderate, >=2 pathogenic comparators = Strong, 1 qualifying likely pathogenic comparator with clinical pathogenicity evidence = Supporting.

Evidence considered

• PM5 requires same-residue missense comparator evidence under TP53 VCEP
• no confirmed codon 196 comparator was available for adjudication

Still missing

• No same-residue TP53 VCEP pathogenic or likely pathogenic comparator was verified.

Sources

Rule

TP53 PP1 requires cosegregation in 3-4 meioses for Supporting, 5-6 for Moderate, and >=7 across >1 family for Strong.

Evidence considered

• available records did not provide family segregation counts
• TP53 VCEP requires 3 or more informative meioses for PP1

Still missing

• No pedigree-level meiosis count was available.

Sources

Rule

TP53 PP4 is based on observed variant allele fraction in the constitutional mosaic range.

Evidence considered

• available records did not provide low-VAF constitutional mosaic observations

Still missing

• No blood or tissue VAF observations were available for TP53 PP4 scoring.

Sources

Rule

TP53 BS2 is based on unrelated unaffected older female carriers from a single source.

Evidence considered

• available records did not contain unaffected-carrier counts required for TP53 BS2

Still missing

• No dataset of unaffected female carriers aged 60 years or older from a single source was available.

Sources

Rule

TP53 BS4 requires lack of segregation in affected family members with Li-Fraumeni-spectrum cancers.

Evidence considered

• available records did not provide informative non-segregation evidence

Still missing

• No family data showing lack of segregation with Li-Fraumeni-spectrum disease were available.

Sources