NM_000251.3:c.630G>A (p.Met210Ile) is a rare missense variant in MSH2 exon 3 observed at extremely low frequency in gnomAD v4.1 (AF = 6.20e-06; 10/1,613,900 alleles; grpmax FAF = 4.37e-05). The grpmax filtering AF exceeds the VCEP PM2_supporting threshold of <2e-05, so PM2 is not met.¹ Computational evidence supports a benign interpretation: the HCI prior probability of pathogenicity is 0.0035, meeting the VCEP BP4_supporting threshold of <0.11. SpliceAI predicts no splicing impact (max delta = 0.04). REVEL score is 0.4 and BayesDel score is -0.059, both consistent with a neutral prediction.² No functional data specific to p.M210I were retrievable from the calibrated deep mutational scan by Jia et al. (2021, PMID 33357406), though this assay is recognized by the VCEP SVI documentation. PS3 and BS3 remain not assessed pending retrieval of the variant-specific LOF score from the study's supplementary data.³ This variant has been reported in ClinVar as Likely benign by Ambry Genetics and Benign by Invitae (ClinVar ID 577710, review status: criteria provided, single submitter, 1-star). However, PP5 and BP6 are explicitly not applicable under the InSiGHT MMR VCEP v2.0, and the review status does not meet 3-star expert panel criteria.⁴ No tumor pathology, segregation, de novo, or case-control data were available for this variant. Criteria dependent on clinical or family-level evidence (PS2, PP1, PP4, BS2, BS4, BP5) could not be assessed.⁵ Under the InSiGHT MMR VCEP v2.0 combining rules, the single BP4_supporting criterion does not meet the threshold for Likely Benign (≥2 supporting benign criteria required per Rule 19) or Benign classification. The variant is classified as a Variant of Uncertain Significance.⁶