PS1
Not assessed: no established pathogenic variant producing the identical amino acid change p.Asn41Ser via a different nucleotide substitution was identified.
PS2
Not assessed: no confirmed de novo occurrence of p.Asn41Ser with verified maternity and paternity was documented.
PS3
Not assessed: no validated functional assay (e.g., kinase activity, Rb phosphorylation) specifically testing p.Asn41Ser was available.
PS4
Not assessed: no case-control enrichment analysis or count of unrelated affected carriers of p.Asn41Ser was available.
PM1
Not met: not in a statistically significant hotspot - cancerhotspots.org found no result and COSMIC shows a single somatic observation (n=1).
PM3
Not assessed: no affected-proband observation in a recessive disorder, no second pathogenic variant, and no phasing evidence were available.
PM5
Not assessed: no pathogenic or likely pathogenic amino acid changes at codon 41 (same-residue comparators) were identified.
PM6
Not assessed: no presumed de novo occurrence of p.Asn41Ser with sufficient phenotype and family context was documented.
PP1
Not assessed: no segregation data - affected or unaffected relatives, informative meioses, or genotype-phenotype results - were available.
PP2
Not assessed: no gene-level missense constraint metric (e.g., missense Z-score or o/e ratio) was available for CDK4.
PP3
Not met: REVEL 0.113, far below the 0.644 pathogenic-supporting cutoff; SpliceAI max delta 0.061.
PP4
Not assessed: no patient-specific phenotype establishing CDK4-related disease specificity was provided.
PP5
Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic submission exists for this variant.
