ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.344T>A (p.Ile115Asn) (rs764120517)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629699 SCV000750655 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-11-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 115 of the MLH1 protein (p.Ile115Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (Invitae). This variant has been reported in the Leiden Open-source Variation Database (PMID: 21520333). An experimental study showed that this missense change leads to an intermediate mutator phenotype in a yeast model (PMID: 15475387). 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 Health, Inc RCV000777086 SCV000912770 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000777086 SCV001181797 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing The p.I115N variant (also known as c.344T>A), located in coding exon 4 of the MLH1 gene, results from a T to A substitution at nucleotide position 344. The isoleucine at codon 115 is replaced by asparagine, an amino acid with dissimilar properties. In one report, p.I115N was determined to have >67% loss of relative mismatch repair activity in a functional screening assay using human-yeast hybrid MLH1 genes (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). Based on internal structural assessment, this alteration results in local structural disruption in the core of the ATPase domain, near the ATP-binding pocket (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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