NM_000535.7:c.2265C>T is a synonymous variant in PMS2 encoding p.(Ile755=) in exon 13 of 15. This variant is present in gnomAD v4.1 at an allele frequency of 0.00574% (92/1,602,058 alleles, including 5 homozygotes) with a grpmax filtering allele frequency of 0.06273%, meeting the MMR VCEP BS1_Strong criterion (>=0.028%).

SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00), meeting the MMR VCEP BP4_Supporting criterion for synonymous variants with no predicted splice alteration (delta <=0.1).

This is a synonymous (silent) variant, meeting the MMR VCEP BP7_Supporting criterion (synonymous variant with no predicted splice impact).

The MMR VCEP PM2_Supporting criterion is not met because the gnomAD v4.1 allele frequency (0.00574%) exceeds the VCEP threshold of <0.002% (<1/50,000 alleles). BA1 is not met as the grpmax FAF (0.06273%) is below the 0.28% threshold.

PVS1, PS1, PM5, PS4, PM1, PM6, PP2, PP5, BP1, BP2, and BP6 are not applicable per MMR VCEP v2.0.0 specification or because the variant type (synonymous) does not satisfy criterion prerequisites.

PS2, PS3, PP1, PP4, BS2, BS3, BS4, and BP5 cannot be assessed due to absence of de novo data, functional studies, cosegregation data, tumor phenotype data, and trans-configuration data in the available evidence.

This variant has been reported in ClinVar as Likely benign by 5 clinical laboratories and as Benign by 4 clinical laboratories (ClinVar Variation ID: 220273). Nine of the 11 PMIDs associated with ClinVar submissions are general guidelines/review articles that do not mention this specific variant; the remaining two (PMID:25741868 and PMID:28492532) were reviewed in full text and do not contain variant-specific evidence.

Applying the MMR VCEP v2.0.0 combining rules: one Benign Strong criterion (BS1) plus two Benign Supporting criteria (BP4, BP7) satisfies both Rule 18 (1 Strong + 1 Supporting => Likely Benign) and Rule 19 (>=2 Supporting => Likely Benign). The combined evidence supports a classification of Likely Benign.