PVS1_Very_Strong: NM_000179.3:c.1135_1139del introduces a premature termination codon at p.Arg379Ter, well within the VCEP boundary of codon 1341. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.¹ PM2_Supporting: This variant is extremely rare in population databases. In gnomAD v4.1, allele frequency is 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), below the VCEP threshold of <0.00002.² PP4_Moderate: The variant has been observed in a patient with two independent MSH6-deficient tumors (endometrial cancer at age 54 and colorectal cancer at age 58), meeting VCEP criteria for 2 independent tumors with IHC loss consistent with the variant gene. PS2_Supporting: The variant was identified as a likely de novo mosaic variant detectable across all three germ layers in a patient with MSH6-deficient Lynch spectrum tumors, meeting 0.5 de novo points under the VCEP PS2 scoring system. Combining 1 Very Strong (PVS1) + 2 Supporting (PM2 + PS2) satisfies VCEP Rule 4 (1 VS + >=2 Sup → Pathogenic). The additional Moderate criterion (PP4) further supports the pathogenic classification.³