PS1
No established pathogenic variant causing the same amino acid change p.(Ala456Val) was identified, so PS1 is not met.
PS2
No confirmed de novo data with verified maternity and paternity were identified, so PS2 was not assessed.
PS3
No validated variant-specific functional study demonstrating a damaging effect for p.(Ala456Val) was identified in the available evidence, so PS3 was not assessed.
PS4
This variant has been reported in COSMIC 2 times, but the local POLE framework requires recurrence in both the COSMIC and TCGA endometrial carcinoma cohorts, a combined endometrial carcinoma count of at least 10, and membership in the established pathogenic set; these requirements are not met for p.(Ala456Val).
PM1
The local POLE framework does not allow PM1 based only on location in the exonuclease domain.
PM3
No trans data with another pathogenic variant in a recessive disorder context were identified, so PM3 was not assessed.
PM5
A different substitution at the same codon, p.(Ala456Pro), is included in the local POLE hotspot set, but the same residue also shows other non-equivalent substitutions in the supplementary tables, including p.A456G and p.A456V.
PM6
No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not assessed.
PP1
No segregation data were identified, so PP1 was not assessed.
PP2
Gene-level evidence required to determine whether missense variation is a common disease mechanism and benign missense variation is low was not identified, so PP2 was not assessed.
PP4
No phenotype data sufficiently specific for a single genetic etiology were identified, so PP4 was not assessed.
PP5
No reputable source classification for this exact variant was identified, so PP5 was not assessed.
