ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1693A>T (p.Ile565Phe) (rs63750062)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160538 SCV000211112 uncertain significance not provided 2017-04-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1693A>T at the cDNA level, p.Ile565Phe (I565F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has been observed to co-occur with a known pathogenic MSH2 variant in a family meeting Amsterdam criteria and in two related individuals with colon cancer (Hutter 1998, Hardt 2011). Takahashi et al. (2007) concluded that MLH1 Ile565Phe is a candidate pathogenic variant based on functional assays completed in yeast while Grabowski et al. (2005) concluded that this variant was most likely not disease causing as mismatch repair immunohistochemistry on a colorectal tumor from an individual harboring this variant showed loss of MSH2 and MSH6 with retention of MLH1. MLH1 Ile565Phe was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile565Phe occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the regions of interaction with PMS2/MLH3/PMS1 and EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ile565Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000234862 SCV000292212 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing
Invitae RCV000627705 SCV000543656 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 565 of the MLH1 protein (p.Ile565Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs63750062, ExAC 0.001%). This variant has been observed in individuals affected with hereditary non-polyposis colorectal cancer (NHPCC)(PMID: 9833759, 21901500, 21404117). However, in one of these individuals a pathogenic allele was also identified in MSH2, which suggests that this c.1693A>T variant was not the primary cause of disease (PMID: 21404117). ClinVar contains an entry for this variant (Variation ID: 89842). Experimental evidence using an in vitro assay suggests that this variant has reduced mismatch repair activity when compared to the MLH1 wild-type protein (PMID: 17510385). 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.
Ambry Genetics RCV000234862 SCV000662094 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160538 SCV001153847 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing

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