What happened, in summary

A woman was diagnosed with triple-negative breast cancer and a separate colon cancer in her mid-30s. Her family history was strongly suggestive of Lynch syndrome. Her sister had developed endometrial cancer with loss of the MSH2 and MSH6 proteins, but standard paired tumor and germline DNA testing did not identify an inherited cause.

Because the family remained unexplained, the woman with breast and colon cancer underwent concurrent DNA and RNA analysis. Testing identified a deep intronic MSH2 variant, c.2458+976A>G. The change created an abnormal splice site and an abnormal RNA transcript that was expected to be broken down before a normal MSH2 protein could be made. The variant was classified as likely pathogenic and was later confirmed in her sister.

This result established an inherited MSH2-related Lynch syndrome diagnosis in the family after routine DNA testing had missed the variant. She was also a carrier with triple-negative breast cancer, but the available evidence does not establish Lynch syndrome as the cause of that breast cancer.

The genetic clarification allowed the family to move from an unresolved cancer history to Lynch-specific screening and risk-reduction planning.