ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2162A>G (p.Tyr721Cys) (rs587778986)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212548 SCV000211121 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2162A>G at the cDNA level, p.Tyr721Cys (Y721C) 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 Tyr721Cys was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Tyr721Cys occurs at a position that is conserved in mammals and is located in the PMS2/MLH3/PMS1 interaction domain (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Tyr721Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160544 SCV000216852 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409675 SCV000488822 uncertain significance Lynch syndrome II 2016-06-23 criteria provided, single submitter clinical testing
Invitae RCV000524278 SCV000543648 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 721 of the MLH1 protein (p.Tyr721Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587778986, ExAC 0.01%). This variant has been reported in an individual affected with acute lymphoblastic leukemia (ALL) (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 90078). 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: "Benign"; Align-GVGD: "Class C55"). 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.
Color RCV000160544 SCV000908656 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781540 SCV000919657 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2162A>G (p.Tyr721Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251160 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.2162A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating an impact of the variant on protein function in the literature. The variant has been reported in one individual with acute lymphocytic leukemia without strong evidence for causality (Zhang_2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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