Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000456258 | SCV000543527 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 14 of the MLH1 protein (p.Thr14Ile). This variant is present in population databases (rs774363593, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 405381). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. 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. |
| Gene |
RCV000478685 | SCV000570081 | uncertain significance | not provided | 2017-03-10 | criteria provided, single submitter | clinical testing | This variant is denoted MLH1 c.41C>T at the cDNA level, p.Thr14Ile (T14I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Thr14Ile was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr14Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Thr14Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000571643 | SCV000669593 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-06 | criteria provided, single submitter | clinical testing | The p.T14I variant (also known as c.41C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 41. The threonine at codon 14 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in a cohort of 274 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Hansen MF et al. Clin. Genet., 2017 Oct;92:405-414). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV004000651 | SCV004830304 | uncertain significance | Lynch syndrome | 2023-06-28 | criteria provided, single submitter | clinical testing |