Variant Views

Massively Parallel Functional Testing of MSH2 Missense Variants Conferring Lynch Syndrome Risk

By Malorye Branca on March, 8 2021


Stay up to date

Primary reference: Jia et al. AJHG. Jan. 7, 2021.

Gene: MSH2.

Lynch syndrome is mainly caused by variants in the DNA mismatch repair factors MSH2, MLH1, MSH6, and PMS2. While patients with a family history of this type of cancer can get screening, one problem is that missense changes comprise 20%-30% of Lynch syndrome variants. These are challenging to interpret, and nearly 90% of clinically observed missense variants in this syndrome are deemed of uncertain significance (VUS).

Researchers from Michigan Medicine performed deep mutational scanning to find such variants' functional status more quickly that the standard approaches. Focusing on MSH2, they carried out a single massively parallel screen in human cells to identify as many loss-of-function missense variants in that gene as possible, at once.  

They report that: "The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians’ interpretations." The large majority (89%) of missense variants were functionally neutral,  which makes it easier to resolve the clinical importance of the ∼1,300 remaining  VUS.


Additional resource:

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Dominguez-Vaentin, et al. Genet Med. 2020. This study aimed to provide age and organ-specific cancer risks for Lynch syndrome according to gene and gender and to determine survival after cancer.  There 1808 prospectively observed cancers. The researchers say that based on their findings "Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most common associated cancers."


Submit your variant news or suggestions to:






Submit a Comment

Stay up to date