ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130610 SCV000185486 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 colon cancer 2018-12-20 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). 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 RCV000212542 SCV000601361 uncertain significance not specified 2017-06-02 criteria provided, single submitter clinical testing
Color RCV000130610 SCV000684762 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212542 SCV000919638 uncertain significance not specified 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1633A>G (p.Thr545Ala) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. A functional study, van der Klift_2015, found the variant to have no affect on splicing. This variant was found in 11/277028 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000087 (11/126568). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). Multiple publications have cited the variant in affected individuals including one publication, Hardt_2011, that reports the variant to co-occur with a pathogenic MSH2 variant (not specified). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance - 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

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