ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.218T>G (p.Leu73Arg) (rs397514684)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213759 SCV000274574 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-23 criteria provided, single submitter clinical testing The p.L73R variant (also known as c.218T>G), located in coding exon 3 of the MLH1 gene, results from a T to G substitution at nucleotide position 218. The leucine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a homozygous state in a male of Polynesian ancestry whose clinical history was consistent with constitutional mismatch repair deficiency (CMMR-D) . This individual developed glioblastoma multiforme (3 years) and T-cell lymphoblastic lymphoma (5.5 years); he was also noted to have near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia and multiple cafe-au-lait spots. The maternal family history was also positive for colorectal cancer (Baas AF et al. Eur. J. Hum. Genet. 2013 Jan; 21(1):55-61). This amino acid position is well conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000466354 SCV000543534 uncertain significance Lynch syndrome 2016-10-04 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 73 of the MLH1 protein (p.Leu73Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (rs397514684, ExAC no frequency). This variant has been reported as being homozygous in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 22692065). ClinVar contains an entry for this variant (Variation ID: 42192). Experimental studies have shown that this mutant causes loss of mismatch repair activity in vitro (PMID: 22692065). In summary, this variant is a rare missense change which has been shown to impair protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000035016 SCV000058656 pathogenic Turcot syndrome 2013-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.