PS1
Not met: the only p.Arg17Trp record (ClinVar 408109) is conflicting VUS/likely benign at 1 star, so no established pathogenic same-amino-acid comparator exists.
PS2
Not assessed: no proband, parental testing or parentage confirmation exists for c.49C>T, so de novo status cannot be established.
PS3
Not assessed: no functional assay of POLD1 p.Arg17Trp was reported, so the generic ACMG PS3 requirement for a well-established damaging-effect study is unmet.
PS4
Not met: no odds ratio or relative risk exists for this variant to compare against the generic PS4 threshold of OR/RR > 5.0.
PM1
Not met: residue 17 of 1107 lies outside POLD1's exonuclease proofreading domain where pathogenic missense variants cluster, and POLD1 R17 is not a reported hotspot.
PM3
Not assessed: no proband genotype, second POLD1 allele, or phase data exists, with zero homozygotes in gnomAD v4.1 (25/1,602,884 alleles).
PM5
Not met: no pathogenic missense at Arg17 exists; ClinVar's only codon-17 POLD1 record is the variant under assessment (408109, VUS/likely benign) and the same-residue harvest found zero comparators.
PM6
Not assessed: no proband or parent-of-origin information exists, so no assumed de novo occurrence can be documented for c.49C>T.
PP1
Not assessed: no pedigree, affected relatives or meioses are available, so co-segregation of c.49C>T with disease cannot be evaluated.
PP3
Not met: REVEL 0.095 is below the >=0.644 PP3 supporting threshold for this missense variant.
PP4
Not met: no proband phenotype or family history is documented, and the only reported phenotype (breast cancer) is not specific for POLD1-associated disease.
PP5
Not met: VCV000408109 has 0 expert-panel submissions (1-star, conflicting ordinary laboratory assertions), so no exact-variant expert-panel classification exists.
