ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.170A>C (p.Lys57Thr) (rs587779955)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212514 SCV000149373 uncertain significance not provided 2013-12-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.170A>C at the cDNA level, p.Lys57Thr (K57T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been reported as a pathogenic variant or a benign polymorphism. MLH1 Lys57Thr 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. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is located in the GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) functional domain, an ATPase domain (Punta 2012). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Lys57Thr is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000115464 SCV000186176 uncertain significance Hereditary cancer-predisposing syndrome 2013-04-17 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
Invitae RCV000816365 SCV000956869 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 57 of the MLH1 protein (p.Lys57Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 127618). 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 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.

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