ClinVar Miner

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

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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 RCV000213338 SCV000273824 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing 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 colorectal neoplasms 2019-11-21 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, 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 RCV000213338 SCV000684889 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-22 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001257463 SCV001434263 uncertain significance Lynch syndrome II 2019-11-25 criteria provided, single submitter clinical testing To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3

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