ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2051A>G (p.Tyr684Cys) (rs267607886)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562804 SCV000669600 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562804 SCV000911480 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-09 criteria provided, single submitter clinical testing
Counsyl RCV000662677 SCV000785385 uncertain significance Lynch syndrome II 2017-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000478138 SCV000565166 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2051A>G at the cDNA level, p.Tyr684Cys (Y684C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been observed in at least one individual with a personal and/or family history of colorectal cancer (Nilbert 2009). MLH1 Tyr684Cys 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 Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Tyr684Cys occurs at a position that conserved across species and is located within the region of interaction with PMS2/MLH3/PMS1 (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance due to insufficient evidence (Thompson 2014). Based on currently available information, it is unclear whether MLH1 Tyr684Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075498 SCV000106494 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524271 SCV000254366 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-16 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 684 of the MLH1 protein (p.Tyr684Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs267607886, ExAC 0.01%). This variant has been reported in an individual affected with colon cancer (PMID: 18566915). ClinVar contains an entry for this variant (Variation ID: 90013). 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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