ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2009A>G (p.Lys670Arg) (rs905983196)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480957 SCV000572323 uncertain significance not provided 2016-11-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2009A>G at the cDNA level, p.Lys670Arg (K670R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Lys670Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MLH1 Lys670Arg occurs at a position that is conserved across species and is located in the PMS2/MLH3/PMS1 interaction domain and PMS1 interactive domain (Pang 1997, Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Lys670Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000539594 SCV000625114 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 670 of the MLH1 protein (p.Lys670Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MLH1-related disease. 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000572513 SCV000662052 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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