Submissions for variant NM_000249.4(MLH1):c.320T>G (p.Ile107Arg)

dbSNP: rs63750507

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075654	SCV000106656	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
GeneDx	RCV000160517	SCV000211083	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MLH1 c.320T>G at the cDNA level, p.Ile107Arg (I107R) at the protein level, and results in the change of an Isoleucine to an Arginine (ATA>AGA). This variant has been published as a recurrent Lynch syndrome (also known as HNPCC) variant in the Finnish population (Nystrom-Lahti 1996, Salovaara 2000, Bala 2001, Raevaara 2005). Multiple functional assays have demonstrated that this mutation has a deleterious effect on protein function with respect to dominant mutator effect, expression, in vitro MMR activity, and sub-cellular localization (Shimodaira 1998, Nystrom-Lahti 2002, Raevaara 2005, Takahashi 2007). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Since Isoleucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ile107Arg occurs at a position that is well conserved across species and is located in the ATP-binding and hydrolysis domain (Raevaara 2005). In addition, In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV001019260	SCV001180592	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-18	criteria provided, single submitter	clinical testing	The p.I107R variant (also known as c.320T>G), located in coding exon 4 of the MLH1 gene, results from a T to G substitution at nucleotide position 320. The isoleucine at codon 107 is replaced by arginine, an amino acid with similar properties. This alteration has been detected in multiple families meeting Amsterdam criteria whose colorectal or endometrial cancers exhibited high microsatellite instability and/or loss of MLH1 protein expression on IHC (Nystrom-Lahti M et al. Hum Mol Genet. 1996 Jun;5(6):763-9; Schweizer P et al. Cancer Res. 2001 Apr 1;61(7):2813-5; Nystrom-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33(2):160-7; Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). Various functional assays have demonstrated deficient mismatch repair activity and reduced mammalian expression in transfected cells (Shimodaira H et al. Nat Genet. 1998 Aug;19(4):384-9; Ellison AR et al. Hum Mol Genet. 2001 Sep 1;10(18):1889-900; Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49; Takahashi M et al. Cancer Res. 2007 May 15;67(10):4595-604). In addition, this alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Kansikas M et al. Hum Mutat. 2011 Jan;32(1):107-15; Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, p.I107R is classified as a pathogenic mutation.