PS2
Not assessed: no de novo occurrence, proband data, or parental testing was available for this variant.
PS3
Not met: no functional studies exist for p.Glu595Lys; OncoKB classifies E595K as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.
PS4
Not assessed: no case-control or cohort data exist for this exact variant, which is absent even from the only validated cohort paper (PMID:35534704).
PM1
Not met: p.Glu595 is not in a mutational hotspot — absent from CancerHotspots.org, and the established MEN2 cysteine hotspots (C609-C634) exclude it.
PM5
Not assessed: no pathogenic alternate missense change at Glu595 (e.g., E595Q/E595A) has been reported for comparison.
PM6
Not assessed: no evidence of a de novo event — no proband data, parental testing, or de novo report exists for this variant.
PP1
Not assessed: no segregation data exist — no pedigree, affected-relative genotyping, or segregation report for this variant.
PP2
Not assessed: no missense constraint data (e.g., gnomAD missense Z-score) was available to confirm a low rate of benign RET missense variation.
PP3
Not met: BayesDel 0.197 is the only pathogenic-leaning score; REVEL 0.47 is indeterminate and SpliceAI max delta 0.00 shows no splice impact, so multiple lines of support are lacking.
PP4
Not assessed: no case-level phenotype documentation exists; the ClinVar record-level conditions are asserted labels with no documented carrier phenotype.
PP5
Not met: no ClinVar expert-panel classification exists for this exact variant (0 expert-panel submissions, 2-star review), so the PP5 trigger is absent.
