ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1146G>C (p.Gln382His) (rs876658801)

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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 RCV000213423 SCV000274511 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000219534 SCV000279330 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1146G>C at the cDNA level, p.Gln382His (Q382H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Gln382His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Gln382His occurs at a position that is not conserved and is not located in a known functional domain (Raevaara 2005, Hardt 2011). 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 Gln382His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459827 SCV000543642 uncertain significance Lynch syndrome 2016-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 382 of the MLH1 protein (p.Gln382His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 230837). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare 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.
Color RCV000213423 SCV000906585 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing

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