ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1669G>A (p.Glu557Lys) (rs63751244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522677 SCV000616783 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1669G>A at the cDNA level, p.Glu557Lys (E557K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Glu557Lys was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Glu557Lys occurs at a position that is conserved in mammals and is located in the regions of interaction with EXO1, PMS2, MLH3, and PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). 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 Glu557Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000548884 SCV000625090 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 557 of the MLH1 protein (p.Glu557Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 449062). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000776165 SCV000911230 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing

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