ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.52C>T (p.Arg18Cys) (rs367654552)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130101 SCV000184931 likely benign Hereditary cancer-predisposing syndrome 2018-01-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification
Color RCV000130101 SCV000537559 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000410307 SCV000489172 uncertain significance Lynch syndrome II 2016-09-09 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121355 SCV000592327 uncertain significance not specified 2016-02-10 criteria provided, single submitter clinical testing
GeneDx RCV000656856 SCV000565138 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.52C>T at the cDNA level, p.Arg18Cys (R18C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in several individuals suspected of having Lynch syndrome, including at least one individual whose tumor showed microsatellite instability (Hardt 2011, Taylor 2013, Chubb 2015, Yurgelun 2015). It was also identified in one healthy individual of Hispanic ancestry (1/118) undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MLH1 Arg18Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within 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 Arg18Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121355 SCV000085534 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000199110 SCV000254370 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 18 of the MLH1 protein (p.Arg18Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs367654552, ExAC 0.003%). This variant has been observed in individuals with colorectal cancer and suspected Lynch syndrome (PMID: 14635101, 21404117, 25980754), and is recorded in the Universal Mutation Database (PMID: 22144684). However, in two individuals it co-occurs with a pathogenic MSH2 variant, suggesting that this c.52C>T substitution in MLH1 was not the primary cause of disease in these individuals. ClinVar contains an entry for this variant (Variation ID: 134656). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656856 SCV000888190 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing

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