September 15, 2021

Xiaoyan Jia, PhD receives 2021 C.W. Cotterman Award

Xiaoyan Jia, PhD receives the 2021 Cotterman Award for his article "Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk". Each September, the Cotterman Award is presented to trainee authors of two articles published in AJHG in the previous year that best represent outstanding scientific contributions to the field of human genetics. The American Society of Human Genetics (ASHG) congratulates the 2021 recipients of the Society’s seven prestigious prizes in human genetics. 

"Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk"

The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed “variants of uncertain significance” (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. 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, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.

Lynch syndrome (MIM: 120435), the first discovered familial cancer syndrome,1 confers predisposition to colorectal and endometrial cancers due to loss of DNA mismatch repair (MMR) and the resulting mutagenic burden.2, 3, 4, 5 Most affected individuals inherit a single loss-of-function variant in one of four MMR factors (MSH2, MLH1, MSH6, PMS2), followed by a somatic “second hit” inactivating the remaining functional copy. Due to high prevalence in the general population (≥1:300),6,7 clear genetic etiology, and potential for prevention through intensified surveillance, pathogenic MMR gene variants are considered clinically actionable.8 Though screening for MMR gene variants is increasingly routine, accurately interpreting them imposes a substantial clinical burden.

Full Article Here: 

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO. Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. Am J Hum Genet. 2020 Dec 17:S0002-9297(20)30439-0. doi:10.1016/j.ajhg.2020.12.003. Epub ahead of print. PMID: 33357406(link is external)