PS1
No pathogenic or likely pathogenic variant resulting in the same amino acid change (p.Ser352Asn) was identified from a different nucleotide change in ClinVar or the literature.
PS2
No de novo observation with confirmed maternity and paternity was identified for this variant in the available evidence.
PS3
No variant-specific functional data are available for p.Ser352Asn.
PS4
No variant-specific case-control prevalence data are available.
PM1
Residue 352 lies within the PWWP domain of DNMT3A (approximately residues 278-427), but cancerhotspots.org does not identify this position as a statistically significant mutational hotspot, and no domain-level mutational enrichment specific to germline disease has been demonstrated for this region in the available evidence.
PM5
No pathogenic or likely pathogenic missense variant at the same codon (Ser352) with a different amino acid change was identified.
PM6
No de novo observation, confirmed or unconfirmed, was identified for this variant in the available evidence.
PP1
No cosegregation data with disease in multiple affected family members is available for this variant.
PP2
Although DNMT3A is associated with Tatton-Brown-Rahman syndrome where missense variants are a known mechanism, no gene-specific missense constraint metric (e.g., missense Z-score) or VCEP-defined PP2 threshold is available to formally apply this criterion.
PP3
Multiple in silico predictors suggest a benign effect: REVEL score 0.098 (well below 0.5 threshold), BayesDel score -0.520724 (negative, supports benign), and SpliceAI max delta 0.29 (below 0.5 threshold for splice-altering prediction).
PP4
No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for DNMT3A-related disease.
PP5
ClinVar classification is uncertain significance with review status 'criteria provided, single submitter,' which does not meet the 3-star expert panel threshold required for PP5 application.
