ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1937A>G (p.Tyr646Cys) (rs35045067)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131964 SCV000187021 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence,Conflicting evidence
Color RCV000131964 SCV000684784 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing
Counsyl RCV000662690 SCV000785415 uncertain significance Lynch syndrome II 2017-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000587551 SCV000211117 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1937A>G at the cDNA level and p.Tyr646Cys (Y646C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). MLH1 Tyr646Cys has been observed in several individuals with Lynch-syndrome associated cancers and/or polyps, with most tumors demonstrating absence of MLH1 protein expression and/or microsatellite instability (Scartozzi 2002, Bianchi 2007, Hardt 2011, Kang 2014, Yurgelun 2015); however, one tumor also demonstrated MLH1 promoter hypermethylation (Nakagawa 2004, Hampel 2005). Several functional studies have investigated this variant, reporting discordant findings. Although MLH1 Tyr646Cys was associated with sufficient mismatch repair activity in two in vitro studies (Raevaara 2005, Drost 2010), an in vivo yeast model reported reduced mismatch repair activity compared with wildtype (Vogelsgang 2009). In addition, while normal localization and protein expression have been described, MLH1 Tyr646Cys has shown defective binding with PMS2 and EXO1 (Belvederesi 2006, Andersen 2012). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Tyr646Cys is located in the region of interaction with PMS2, MLH3, PMS1 and EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Tyr646Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000030218 SCV000052885 uncertain Lynch syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587551 SCV000696136 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1937A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys located in the PMS2/MLH3/PMS1 interacting region (Raevaara 2005) and EXO1 (UniProt). 4/4 in-silico tools (SNPs&GO not captured here due to low reliability tool) predict a "damaging" outcome. This variant is found in 4/121804 control chromosomes including the large and broad populations from ExAC at a frequency of 0.0000328, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007105) in this gene. Based on its low frequency in general population coupled with a few variant occurrences, it is unknown whether this variant is a rare polymorphism or has a role in disease. This variant has been reported in multiple patients with HNPCC or HNPCC-related cancers and one astrocytoma tumor sample as a somatic occurrence, however without clear evidences supporting for pathogenicity. There are no reported cosegregation studies for this variant at this time. In vitro functional studies provided conflicting results in relation to binding of this MLH1 Y646C mutant with PMS2 (Raevaara_2005, Belvederesi_2006, Drost_2011, Andersen_2012). Localization and expression of this variant and MMR activity of this mutant were found to be normal (Raevaara_2005, Belvederesi_2006, Vogelsang_2009, Drost_2011, Andersen_2012). However, in vitro measurement of mutation rate of this mutant was highly impaired (Vogelsang_2009) and it was also defective in binding with Exo1 protein (Andersen_2012). Thus based on the functional assays, it is uncertain whether this variant leads to functional impairment or not. Multiple clinical laboratories (via ClinVar) and reputable databases have classified this variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000524258 SCV000254364 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 646 of the MLH1 protein (p.Tyr646Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs35045067, ExAC 0.006%). This variant has been reported in individuals from suspected Lynch syndrome families (PMID: 11870161, 16083711, 16724012), in individuals affected with colon cancer (PMID: 17250665, 21404117), and in individuals with a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). Additionally, this variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 36545). While some experimental studies have shown that this missense change disrupts interaction with PMS2 (PMID: 22753075, 16724012), another study reports normal PMS2 interaction (PMID: 16083711). Experimental studies have also reported that this variant exhibits normal subcellular localization and displays MMR activity comparable to the wild-type protein (PMID: 16083711, 22753075, 20020535), although another study reported that this variant confers an elevated mutation rate in yeast (PMID: 19863800). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587551 SCV000889393 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131964 SCV000788019 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-10 no assertion criteria provided clinical testing

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