NM_000179.3:c.3312del (p.Phe1104LeufsTer11) is a frameshift deletion in exon 5 of MSH6 predicted to introduce a premature termination codon at codon 1104, well within the VCEP threshold of codon 1341 for PVS1_VeryStrong.

This variant is extremely rare in population databases, with a single heterozygous observation in gnomAD v4.1 (AF = 6.20e-07; 1/1,614,052 alleles) and absent from gnomAD v2.1, meeting PM2_Supporting per MSH6 VCEP thresholds (AF <0.00002).

This variant has been classified as Pathogenic by the InSiGHT expert panel in ClinVar (Variation ID: 89371) and by six clinical laboratories. The ClinVar record cites PMIDs 16360201, 18269114, 20487569, and 27601186; however, full-text confirmation of variant-specific mention could not be verified for these papers, and PP5 is not applicable per VCEP guidance.

No de novo observations (PS2), calibrated functional assay data (PS3), segregation data (PP1/BS4), or tumor phenotype data (PP4/BP5) were identified in the literature for this specific variant.

Applying the MSH6 VCEP v2.0.0 combination rules: PVS1_VeryStrong alone meets Rule 1 (>=1 PVS1_VeryStrong), yielding a classification of Pathogenic.