ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.848A>G (p.Tyr283Cys) (rs201931669)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223129 SCV000277270 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000588139 SCV000570504 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.848A>G at the cDNA level, p.Tyr283Cys (Y283C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Tyr283Cys was not observed at a significant allele frequency in the 1000 Genomes Project. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Tyr283Cys occurs at a position that is conserved across species and is not located in a known functional domain (Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Tyr283Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000551542 SCV000625202 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 283 of the MLH1 protein (p.Tyr283Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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: 232984). 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.
Integrated Genetics/Laboratory Corporation of America RCV000588139 SCV000696185 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.848A>G (p.Tyr283Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121410 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588139 SCV000889406 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588139 SCV001248018 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001145069 SCV001305707 uncertain significance Lynch syndrome II 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV000223129 SCV001353107 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-03 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.