ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.595G>C (p.Glu199Gln) (rs63749887)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165198 SCV000215910 likely benign Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Other data supporting benign classification;No disease association in appropriately sized case-control study(ies)
GeneDx RCV000218794 SCV000279076 uncertain significance not provided 2016-07-05 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.595G>C at the cDNA level, p.Glu199Gln (E199Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). In vitro functional studies of this variant showed mismatch repair activity and dominant mutator effect comparable to wild-type (Takahashi 2007). This variant was also observed in a healthy control with no reported family history of colon cancer (Wahlberg 1999). MLH1 Glu199Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Glu199Gln occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Glu199Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627702 SCV000543610 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 199 of the MLH1 protein (p.Glu199Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs63749887, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a healthy control individual with no family history of colorectal cancer (PMID: 10495924). ClinVar contains an entry for this variant (Variation ID: 90293). An experimental study has shown that this variant does not affect MLH1 mismatch repair activity or protein expression in vitro (PMID: 17510385) 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.
Color RCV000165198 SCV000684851 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-09 criteria provided, single submitter clinical testing
Counsyl RCV000663260 SCV000786488 uncertain significance Lynch syndrome II 2018-05-11 criteria provided, single submitter clinical testing

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