Overview

Purpose: Testing for MLH1, MSH2, and MSH6 genes is often conducted to evaluate the risk of Lynch syndrome and related cancers. These genes are crucial for proper DNA repair, and mutations can lead to an accumulation of genetic errors that increase cancer risk.

Indications for Testing:

• Family history of Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian).
• Personal history of cancers associated with Lynch syndrome, especially at a young age.
• Tumor characteristics indicative of Lynch syndrome, such as microsatellite instability (MSI) or loss of MMR protein expression.

Risk Assessment

Normal Function: MLH1, MSH2, and MSH6 genes encode proteins involved in repairing mismatched DNA. Proper function of these proteins helps prevent genetic mutations that can lead to cancer.

Increased Risk: Mutations in these genes impair DNA repair, leading to an increased risk of Lynch syndrome and associated cancers:

• MLH1: Mutations can lead to a higher risk of colorectal, endometrial, ovarian, and other cancers.
• MSH2: Mutations are linked to similar risks as MLH1, often also affecting other cancers.
• MSH6: Mutations are associated with colorectal and endometrial cancers, with potentially different cancer risks compared to MLH1 and MSH2.

Normal Range

Normal Range: A “normal” result indicates that no pathogenic mutations are found in the MLH1, MSH2, or MSH6 genes. In genetic testing, this means the genes are functioning as expected, and there is no identified mutation associated with an increased cancer risk.

Interpretation

Pathogenic Mutations: If a mutation is detected, the result is interpreted as follows:

• Pathogenic: The mutation is known to increase cancer risk significantly.
• Likely Pathogenic: The mutation is likely to increase cancer risk, but with some uncertainty.
• Variants of Uncertain Significance (VUS): The impact of the mutation on cancer risk is unclear, and further research may be needed to determine its significance.

Negative Result: No pathogenic mutations are detected in MLH1, MSH2, or MSH6. However, this does not entirely rule out Lynch syndrome or other genetic conditions, especially if clinical or family history still suggests a high risk.

Sample Type

Sample Type: The genetic test for MLH1, MSH2, and MSH6 typically requires a sample of DNA, which can be collected in several ways:

• Blood Sample: Most commonly used; collected via a standard blood draw.
• Saliva Sample: Occasionally used, though less common.
• Buccal Swab: A swab from the inside of the cheek can also be used to collect cells for DNA analysis.