Science In 60: Tumor Characteristics Provide Evidence for Mismatch Repair Variant Pathogenicity

It is estimated that as many as 1 in 300 people may carry a gene mutation associated with Lynch syndrome. This is important to know because Lynch syndrome also puts individuals at a higher risk for many other cancers including colon, uterine, ovarian, pancreatic, stomach, liver and bladder cancer. The good news is genetic testing can determine whether a person has these mutations. Increasingly, IHC or MSI testing is being offered to anyone diagnosed with colorectal cancer to look for signs that may indicate Lynch syndrome.

Pathogenic germline mutations in mismatch repair (MMR) genes increase an individuals’ risk for Lynch syndrome and other cancers. Tumor microsatellite instability (MSI) and immunohistochemical (IHC) analyses are often used to screen patients at risk for Lynch syndrome.

In our recent study with 3,320 patients with this data, we computed the likelihood of a MMR variant being pathogenic based on MSI/IHC results, and found that MMR mutations are strongly associated with abnormal or unstable tumor characteristics. By leveraging the likelihood of known benign and pathogenic MMR variants, we were able to identify 15 VUSs that may potentially be reclassified as benign or likely benign.

These results demonstrate that tumor characteristics such as MSI and IHC provide evidence for assessing germline variant pathogenicity, and can be used independently or in conjunction with other evidence to inform variant classification.

Our results help healthcare provider’s quantity a patient’s disease risk and inform medical management decisions.



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