ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.347C>A (p.Thr116Lys) (rs63750465)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235173 SCV000149390 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.347C>A at the cDNA level, p.Thr116Lys (T116K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant has been observed in at least one family with cancer history suggestive of Lynch syndrome (Tournier 2008). Additionally, Tournier et al. (2008) found this variant to have no effect on splicing in an ex vivo splicing assay. MLH1 Thr116Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Thr116Lys occurs at a position that is conserved across species and is located within the ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as a variant of uncertain significance based on insufficient evidence (Thompson 2014). Based on currently available evidence, it is unclear whether MLH1 Thr116Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115481 SCV000186795 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000524292 SCV000261100 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 116 of the MLH1 protein (p.Thr116Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Lynch syndrome (PMID: 18561205), and in an individual in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 90176). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000410226 SCV000489667 uncertain significance Lynch syndrome II 2016-11-02 criteria provided, single submitter clinical testing
Color RCV000115481 SCV000684819 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764481 SCV000895552 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780414 SCV000917641 uncertain significance not specified 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.347C>A (p.Thr116Lys) variant causes a missense change located in the Histidine kinase/HSP90-like ATPasedomain of the protein (InterPro) involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/277164 control chromosomes (gnomAD) at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). Tournier_2008 found this variant to have no effect on splicing in an ex vivo splicing assay. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).

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