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 likely benign Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
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 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000411981 SCV000489159 uncertain significance Lynch syndrome II 2016-08-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131299 SCV000537551 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 379 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 14635101, 21404117) and mesothelioma (PMID: 28687356). This variant has also been reported in individuals whose phenotypes suggest this variant to be unlikely pathogenic (ClinVar variation ID: 142276). This variant has been identified in 15/282670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587171 SCV000601345 uncertain significance not provided 2019-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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