ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1633A>G (p.Thr545Ala) (rs267607840)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130610 SCV000185486 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000656863 SCV000211111 uncertain significance not provided 2018-04-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1633A>G at the cDNA level, p.Thr545Ala (T545A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has been observed in at least two individuals; one suspected of having a hereditary form of colorectal cancer, while the other is noted as meeting Amsterdam II criteria and also harboring a known pathogenic MSH2 variant (Nilbert 2008, Hardt 2011). MLH1 Thr545Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005) Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Although this variant demonstrated splicing comparable to wild-type in a minigene assay and in patient RNA analysis, the impact that this variant has on protein function was not evaluated (van der Klift 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MLH1 Thr545Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524244 SCV000261240 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 545 of the MLH1 protein (p.Thr545Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs267607840, ExAC 0.009%). This variant has been reported in an individual from the Danish HNPCC (hereditary non-polyposis colorectal cancer) register (PMID: 18566915) and an individual affected with breast and/or ovarian cancer (PMID: 26898890). It has also been observed in an individual with HNPCC that meets the Amsterdam-II criteria; however, a pathogenic MSH2 variant was also reported to co-occur, suggesting that this c.1633A>G substitution in MLH1 was not the primary cause of disease in this individual (PMID: 21404117). ClinVar contains an entry for this variant (Variation ID: 89812). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000656863 SCV000601361 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing
Color RCV000130610 SCV000684762 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212542 SCV000919638 uncertain significance not specified 2019-12-09 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1633A>G (p.Thr545Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251320 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (4e-05 vs 0.00071), allowing no conclusion about variant significance. c.1633A>G has been reported in the literature in individuals affected with cancer (e.g. Nilbert_2009, Hardt_2011, Caminsky_2016) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with a pathogenic variant in MSH2 was reported by Hardt_2011 (variant not specified), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212542 SCV000691863 uncertain significance not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000606136 SCV000734268 uncertain significance Lynch syndrome II no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.