ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2213G>A (p.Gly738Glu) (rs148317871)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767194 SCV000211122 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2213G>A at the cDNA level, p.Gly738Glu (G738E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant was observed in an individual with polyposis and in a patient with breast and/or ovarian cancer (Shirts 2016, Cock-Rada 2018). MLH1 Gly738Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Gly738Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000030221 SCV000266179 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000524281 SCV000284052 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 738 of the MLH1 protein (p.Gly738Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs148317871, ExAC 0.01%). This variant has been reported in an individual with colorectal polyposis and a family history of pancreatic cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 36548). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000411992 SCV000488721 uncertain significance Lynch syndrome II 2016-05-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573289 SCV000662026 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000160545 SCV000696152 uncertain significance not specified 2019-10-03 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2213G>A (p.Gly738Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Five 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 251268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2213G>A has been reported in the literature in one individual with polyposis who had first degree relative(s) with pancreatic cancer and in individual(s) affected with breast and/or ovarian cancer (Shirts_2016, Cock-Rada_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with a pathogenic variant has been reported (MSH2 c.1915C>T, p.His639Tyr; LCA). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000767194 SCV001134306 uncertain significance not provided 2019-02-22 criteria provided, single submitter clinical testing
Color RCV000573289 SCV001354157 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-16 criteria provided, single submitter clinical testing

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.