NM_002944.2:c.5825G>A (p.Arg1942Gln) is a missense variant in exon 37 of the ROS1 gene, encoding a receptor tyrosine kinase implicated in familial lung cancer and hereditary breast cancer.¹ This variant is present at extremely low frequency in gnomAD v4.1 (AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes) and is absent from gnomAD v2.1. The grpmax filtering allele frequency is 8.75e-06, well below the 0.1% threshold for PM2 at supporting strength.² In silico predictors are predominantly deleterious: REVEL score 0.706 (pathogenic-leaning) and SpliceAI max delta 0.99 (predicts acceptor gain with potential splice-altering effect). PP3 is applied at supporting strength.³ The variant is absent from ClinVar and COSMIC. No variant-specific functional studies, de novo reports, segregation data, or case-control analyses are available in the case materials.⁴ PVS1 is not applicable as this is a missense variant. The variant does not lie at a canonical splice consensus position and falls outside the null-variant buckets defined by the ClinGen PVS1 framework (PMC6185798).⁵ Only two supporting-level criteria (PM2_Supporting, PP3) are met. Per the ACMG/AMP 2015 combination rules, two supporting criteria are insufficient to reach a Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).⁶