ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.666T>G (p.Asn222Lys)

gnomAD frequency: 0.00001  dbSNP: rs751719069
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
Color Diagnostics, LLC DBA Color Health RCV001181967 SCV001347233 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing This missense variant replaces asparagine with lysine at codon 222 of the MLH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251086 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.
Invitae RCV001320907 SCV001511715 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-04-12 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: 922107). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs751719069, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 222 of the MLH1 protein (p.Asn222Lys).
Ambry Genetics RCV001181967 SCV002663962 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-03 criteria provided, single submitter clinical testing The p.N222K variant (also known as c.666T>G), located in coding exon 8 of the MLH1 gene, results from a T to G substitution at nucleotide position 666. The asparagine at codon 222 is replaced by lysine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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.