NM_000251.3:c.2458+8C>G is an intronic variant in MSH2 located at position +8 of intron 14. SpliceAI predicts no splicing impact (max delta score 0.04), satisfying BP4 at Supporting benign strength per the InSiGHT MSH2 VCEP v2.0.0.

This variant is present in gnomAD v4.1 at a low frequency (33/1,613,836 alleles; AF=2.04e-05; grpmax FAF=8.99e-05) but does not meet the VCEP PM2 threshold (<0.00002) nor BS1 (≥0.0001), falling in an intermediate frequency range that neither supports nor refutes pathogenicity under VCEP rules.

As an intronic variant at position +8 (beyond the +7 boundary), BP7 applies at Supporting benign strength per VCEP rules. The variant may satisfy both BP7 and BP4.

This variant has been reported in ClinVar (ClinVar ID 135857) as Likely benign by 10 clinical laboratories and as Benign by 1 clinical laboratory, with no expert panel review to date. No published studies have specifically evaluated this variant for functional effects, segregation, or tumor phenotype.

No evidence is available for PVS1 (not a null variant), PS2 (no de novo reports), PS3 (no functional studies), PP1 (no segregation data), PP4 (no tumor MSI/IHC data), BS2 (no trans co-occurrence), BS3 (no laboratory functional assay), BS4 (no lack-of-segregation data), or BP5 (no tumor phenotype data).

Applying the InSiGHT MSH2 VCEP v2.0.0 combining rules: two Supporting benign criteria (BP4 + BP7) are met, satisfying Rule 19 (≥2 Benign Supporting → Likely Benign).