ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.652T>C (p.Ser218Pro)

gnomAD frequency: 0.00001  dbSNP: rs750650349
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000475778 SCV000543604 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564654 SCV000662013 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-25 criteria provided, single submitter clinical testing The p.S218P variant (also known as c.652T>C), located in coding exon 8 of the MLH1 gene, results from a T to C substitution at nucleotide position 652. The serine at codon 218 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000564654 SCV000911477 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-16 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 218 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 2/251136 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.
Mendelics RCV000987155 SCV001136382 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280631 SCV001467862 uncertain significance not specified 2020-12-03 criteria provided, single submitter clinical testing Variant summary: MLH1 c.652T>C (p.Ser218Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.652T>C has been reported in the literature in an unaffected individual (Kraemer_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000987155 SCV004192977 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-06-23 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000657 SCV004840886 uncertain significance Lynch syndrome 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 218 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 2/251136 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.

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.