ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1474G>A (p.Ala492Thr) (rs63751145)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132236 SCV000187319 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212538 SCV000211105 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1474G>A at the cDNA level, p.Ala492Thr (A492T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has been observed in several individuals with early onset colorectal cancer, one of whom was also found to carry a pathogenic MSH6 variant (Moslein 1996, Steinke 2008). A yeast two-hybrid assay demonstrated intact PMS2 & EXO1 binding (Kondo 2003) and an in vitro MMR complementation assay showed sufficient MMR repair activity and MLH1 expression and stability (Takahashi 2007). However; another yeast-based functional assay exhibited a reduction in dominant mutator effect (Shimodaira 1998). Furthermore, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance (Thompson 2014). MLH1 Ala492Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Ala492Thr is located in 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, support a deleterious effect. Based on currently available information, it is unclear whether MLH1 Ala492Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000524241 SCV000254350 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 492 of the MLH1 protein (p.Ala492Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs63751145, ExAC 0.006%). This variant has been reported in individuals affected with colon cancer and rectal cancer (PMID: 8872463, 18301448, 8895729), however, in one of these individuals, a pathogenic allele was identified in the MSH6 gene, which suggests that this c.1474G>A substitution in MLH1 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 89750). Experimental studies have shown that this missense change leads to a dominant mutator effect deficiency in a yeast assay that may not be a direct assessment of pathogenicity (PMID: 9697702). In addition, this missense change has been shown to have no major impact on MLH1 interaction with its partners, and different studies report conflicting results regarding the effect of this variant on mismatch repair activity (PMID: 12810663, 17510385, 17192056, 18373977). 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.
Color RCV000132236 SCV000689816 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000075224 SCV000788235 likely benign Lynch syndrome 2018-04-01 criteria provided, single submitter research The MLH1 variant designated as NM_000249.3: c.1474G>A (p.Ala492Thr) is classified as likely benign. Pretest probability for pathogenicity was less than 0.1 based on computer prediction with PolyPhen2 of 0.033 and MAPP of 2.75 (Thompson et al. 2013, PMID:12900794). Family history analysis of one observed family revealed no Lynch syndrome-associated cancers in multiple individuals tested to have the variant. Cosegregation analysis of the same observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of 0.19 to 1 that this allele explains cancers in the family (Thompson et al. 2003, PMID:1290079), which provides evidence against pathogenicity. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MLH1 function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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