ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.821A>G (p.Lys274Arg) (rs769958855)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481241 SCV000565147 uncertain significance not provided 2015-02-24 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.821A>G at the cDNA level, p.Lys274Arg (K274R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Lys274Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MLH1 Lys274Arg occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). 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 Lys274Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000558471 SCV000625200 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 274 of the MLH1 protein (p.Lys274Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs769958855, ExAC 0.001%). This variant has been observed in an individual affected with colorectal cancer, as well as in control individuals from the Icelandic population (PMID: 28466842). ClinVar contains an entry for this variant (Variation ID: 418300). 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.
Ambry Genetics RCV000563768 SCV000669583 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764482 SCV000895553 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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