ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.554T>G (p.Val185Gly) (rs63750515)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075761 SCV000106769 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, 1 MSI-H tumour & 1 tumour with MLH1 immunoloss, co-segregation with disease & absent in 1000 genomes. Multifactorial likelihood analysis posterior probability >0.99.
GeneDx RCV000218149 SCV000279073 likely pathogenic not provided 2016-02-23 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.554T>G at the cDNA level, p.Val185Gly (V185G) at the protein level, and results in the change of a Valine to a Glycine (GTA>GGA). In vitro mismatch repair (MMR) assays have demonstrated deficient MMR activity for this variant (Trojan 2002, Raevaara 2005, Takahashi 2007). MLH1 Val185Gly has also been shown to affect subcellular localization and interaction with protein partners, and to reduce MLH1 protein expression (Kondo 2003, Raevaara 2005). Immunohistochemistry (IHC) performed on at least one colorectal tumor has demonstrated loss of MLH1 and PMS2 (Toon 2013). Additionally, the clinical histories of several published cases are consistent with Lynch syndrome (Scott 2001, Chao 2008, Chubb 2015). MLH1 Val185Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Glycine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val185Gly occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain (Pang 1997). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider MLH1 Val185Gly to be a likely pathogenic variant.

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