Muir-Torre Syndrome Associated With a Cryptic Intronic MSH2 Variant Identified via Whole-Genome Sequencing: A Case Report.

Germline intronic MSH2 variant (NM_000251.3:c.2459-12A>G) missed by standard multigene panel testing, causing aberrant splicing with an 11-bp insertion and concordant loss of MSH2 and MSH6 expression.

A 47-year-old man presented with synchronous axillary sebaceous carcinoma and colonic medullary carcinoma. Initial germline multigene panel testing identified no pathogenic variant despite strong pathological suspicion of Muir-Torre syndrome. Immunohistochemistry showed concordant loss of MSH2 and MSH6 expression in both anatomically distinct tumours, favouring an underlying germline defect over two independent biallelic somatic events. Whole-genome sequencing then identified a germline intronic MSH2 variant (NM_000251.3:c.2459-12A>G), and RNA analysis confirmed aberrant splicing with an 11-bp insertion. The authors conclude that a concordant mismatch repair protein loss pattern across multiple tumours justifies reconsidering a negative panel result and pursuing comprehensive genomic investigation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a textbook illustration of what a panel costs: the variant lies 12 bp from a junction, outside captured or reported regions, and one more patient is wrongly labelled Lynch-like. The transferable lesson is not to widen the panel but to accept that a concordant immunohistochemical pattern across two distinct tumours is sufficient grounds to move to genome sequencing — and then to carry through to RNA analysis, the only step here that turns an intronic change into a causal variant. This remains a single case: the value is methodological, not epidemiological, and it supports no estimate of the share of deep intronic variants among Lynch-like cases.

Analysis by Dr Thibaut Benquey