Hamzaoui et al. identified two relatives who carried both POLE p.K425R (VUS) and MSH2 c.942+3A>T (pathogenic), in a family with multiple CRC-affected members diagnosed at extremely young ages (range: 19–33), suggesting a cumulative effect of the two variants.35 Whether the aggregation of cancer in these families is explained only by the pathogenic variants in ATM, CHEK2, or MSH2, or the combined effect with the POLE/D1 variants (all of them classified as VUS until now), remains to be elucidated. Here, MSH2 is linked to cancer.