ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1136A>G (p.Tyr379Cys) (rs143009528)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000781987 SCV000920443 likely benign Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.005)
Ambry Genetics RCV000131299 SCV000186271 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Conflicting evidence
GeneDx RCV000587171 SCV000211101 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1136A>G at the cDNA level, p.Tyr379Cys (Y379C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been observed in individuals with colorectal cancer, gastric cancer, ovarian cancer, renal cancer, breast cancer, sarcoma, and malignant pleural mesothelioma (Taylor 2003, Hardt 2011, Pal 2012, Ballinger 2016, Caminsky 2016, Betti 2017, Yehia 2018). MLH1 Tyr379Cys was observed at an allele frequency of 0.015% (5/34,416) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may result in the creation of a cryptic splice donor site upstream of the natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MLH1 Tyr379Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196668 SCV000254346 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 379 of the MLH1 protein (p.Tyr379Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs143009528, ExAC 0.02%). This variant has been reported in individuals affected with colorectal cancer and ovarian cancer (PMID: 14635101, 23047549), and an individual with sporadic malignant pleural mesothelioma who was noted to have had occupational asbestos exposure (PMID: 28687356). ClinVar contains an entry for this variant (Variation ID: 142276). 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 C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000411981 SCV000489159 uncertain significance Lynch syndrome II 2016-08-29 criteria provided, single submitter clinical testing
Color RCV000131299 SCV000537551 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212531 SCV000601345 uncertain significance not specified 2017-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587171 SCV000696096 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1136A>G (p.Tyr379Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict the variant to create a cryptic splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5/121182 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant has been reported in patients with HNPCC, extra colonic cancer and epithelial ovarian cancer patients, however, without strong evidence for the causitive relationship between the variant and diseases. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.

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