ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.94A>G (p.Ile32Val) (rs2020872)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524324 SCV000259953 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 32 of the MLH1 protein (p.Ile32Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs2020872, ExAC 0.01%). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 36560). Experimental studies in yeast have shown that this missense change does not impact MLH1 binding to PMS2 or EXO1, though it reduces the interaction with MRE11 (PMID: 12810663, 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.
GeneDx RCV000217828 SCV000279736 uncertain significance not provided 2015-12-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.94A>G at the cDNA level, p.Ile32Val (I32V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). Yeast two hybrid assays have indicated that MLH1 Ile32Val did not significantly impact MLH1-PMS2 and MLH1-EXO1 interactions in comparison to wild type (Zhao 2008, Kondo 2012). MLH1 Ile32Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile32Val occurs at a position that is conserved in mammals and is located in the ATPase domain (Raevaara 2005, Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, with published computational models suggesting that this variant is not pathogenic (Ali 2012). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant to be of uncertain significance due to insufficient evidence. Based on currently available evidence, it is unclear whether MLH1 Ile32Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568967 SCV000662074 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Mendelics RCV000030233 SCV000837992 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000568967 SCV000903216 likely benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030233 SCV000052900 uncertain significance Lynch syndrome 2015-10-02 no assertion criteria provided clinical testing

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