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 No disease association in appropriately sized case-control study(ies);Other data supporting benign classification
GeneDx RCV000218794 SCV000279076 likely benign not provided 2020-02-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17510385, 10495924, 16995940, 18383312, 26333163, 23741719, 29505604, 11574484, 28416821)
Invitae RCV000627702 SCV000543610 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-28 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 Health, Inc 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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