ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1502T>G (p.Ile501Ser) (rs587780679)

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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 RCV000217500 SCV000277910 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000217500 SCV000689819 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000662470 SCV000784962 uncertain significance Lynch syndrome II 2017-02-22 criteria provided, single submitter clinical testing
GeneDx RCV000486481 SCV000573032 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1502T>G at the cDNA level, p.Ile501Ser (I501S) at the protein level, and results in the change of an Isoleucine to a Serine (ATT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Ile501Ser was not observed in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1 as well as PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Ile501Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122971 SCV000166245 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 501 of the MLH1 protein (p.Ile501Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 135847). 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: "Benign"; Align-GVGD: "Class C25"). 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.

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