ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.626A>C (p.Asn209Thr)

dbSNP: rs150478207
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206240 SCV000259686 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-06-27 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 219679). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28726808). This variant is present in population databases (rs150478207, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 209 of the MLH1 protein (p.Asn209Thr).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507499 SCV000601405 uncertain significance not specified 2017-04-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV001025057 SCV001187179 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter clinical testing The p.N209T variant (also known as c.626A>C), located in coding exon 8 of the MLH1 gene, results from an A to C substitution at nucleotide position 626. The asparagine at codon 209 is replaced by threonine, an amino acid with similar properties. This alteration has been identified 1/302 individuals with pancreatic cancer. (Chaffee KG et al. Genet Med, 2018 01;20:119-127). This amino acid position is not 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.
Sema4, Sema4 RCV001025057 SCV002528761 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-21 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003997577 SCV004835307 uncertain significance Lynch syndrome 2023-09-17 criteria provided, single submitter clinical testing This missense variant replaces asparagine with threonine at codon 209 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251242 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.