ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.350C>G (p.Thr117Arg) (rs63750781)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000622257 SCV000106667 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.986
Invitae RCV000075665 SCV000543559 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 117 of the MLH1 protein (p.Thr117Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22034109), and families with suspected Lynch syndrome (PMID: 8592341, 15713769, 21404117). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 90178). Several experimental studies have shown that this missense change abolishes MLH1 mismatch repair activity and interactions with PMS2 and EXO1 in cell-based assays (PMID: 11555625, 9697702, 12810663). A different missense substitution at this codon (p.Thr117Met) is reported to be deleterious (PMID: 17135187, 19267393, 20233461). This indicates that the threonine residue is important for MLH1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202256 SCV000565143 likely pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.350C>G at the cDNA level, p.Thr117Arg (T117R) at the protein level, and results in the change of a Threonine to an Arginine (ACG>AGG). This variant has been identified in at least four individuals from three Hereditary Nonpolyposis Colorectal Cancer kindreds, with studied tumors demonstrating microsatellite instability and loss of MLH1 expression on immunohistochemistry (Buerstedde 1995, Casey 2005, Hardt 2011, Buerki 2012). Functional studies have demonstrated decreased MLH1 expression and LexA binding, defective mismatch repair activity, and no or reduced dominant mutator effect, consistent with pathogenicity (Shimodaira 1998, Ellison 2001, Kondo 2003, Takahashi 2007). MLH1 Thr117Arg 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 Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Thr117Arg occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the ATPase domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MLH1 Thr117Arg to be a likely pathogenic variant.
Ambry Genetics RCV000569088 SCV000676017 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-17 criteria provided, single submitter clinical testing The p.T117R variant (also known as c.350C>G), located in coding exon 4 of the MLH1 gene, results from a C to G substitution at nucleotide position 350. The threonine at codon 117 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in multiple families affected with colon cancer meeting Amsterdam diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC) syndrome (Buerstedde JM et al. J. Med. Genet. 1995;32:909-12; Ellison A et al Hum Mol Genet. 2001 Sep 1;10(18):1889-900; Heinimann K et al Cancer. 1999 Jun 15;85(12):2512-8). This alteration has also been detected in an individual meeting Bethesda criteria, with colon cancer diagnosed at 52 years and tumor studies demonstrating MSI-H and decreased MLH1 staining (less than 10%) on IHC (Hardt K et al. Fam. Cancer 2011; 10:273-84). Furthermore, in one in vitro functional study, this alteration was shown to decrease MMR activity to 25.2% and reduce MLH1 expression to 25-75% in comparison to the wild-type; PMS2 expression was also reduced (Takahashi M et al. Cancer Res. 2007; 67:4595-604). An earlier functional study using a yeast two-hybrid assay also demonstrated decreased beta-galactosidase activity compared to the wild type (Kondo E et al. Cancer Res. 2003; 63:3302-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202256 SCV000257097 pathogenic not provided no assertion criteria provided research

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