ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.991G>A (p.Glu331Lys) (rs550914672)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213338 SCV000273824 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000222012 SCV000279886 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.991G>A at the cDNA level, p.Glu331Lys (E331K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Glu331Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (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 Glu331Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000537429 SCV000625216 uncertain significance Hereditary nonpolyposis colon cancer 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 331 of the MLH1 protein (p.Glu331Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs550914672, ExAC 0.003%). 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: 230317). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000213338 SCV000684889 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing

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