ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.107T>C (p.Ile36Thr)

gnomAD frequency: 0.00001  dbSNP: rs267607707
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699687 SCV000828410 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 36 of the MLH1 protein (p.Ile36Thr). This variant is present in population databases (rs267607707, gnomAD 0.003%). 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: 577034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Ambry Genetics RCV001009839 SCV001169955 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing The p.I36T variant (also known as c.107T>C), located in coding exon 1 of the MLH1 gene, results from a T to C substitution at nucleotide position 107. The isoleucine at codon 36 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001009839 SCV001344986 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-08 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 36 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/250752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV003472231 SCV004195025 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-10-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999695 SCV004835238 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 36 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/250752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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