Submissions for variant NM_000249.4(MLH1):c.1136A>G (p.Tyr379Cys)

dbSNP: rs143009528

Total submissions: 12

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2024-01-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000411981	SCV000489159	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-08-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131299	SCV000537551	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	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 breast and/or ovarian cancer (PMID: 23047549, 26898890), colorectal cancer (PMID: 14635101, 21404117), melanoma (25148578), sarcoma (PMID: 27498913), and mesothelioma (PMID: 28687356). This variant has also been reported in individuals whose phenotypes suggest that this variant is not likely to be pathogenic (ClinVar SCV004018102.1). 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	2023-08-01	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals breast cancer (PMID: 33471991 (2021), 26898890 (2016), ovarian cancer (PMID: 23047549 (2012)), suspected Lynch syndrome PMID: 21404117 (2011), 14635101 (2003)), as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). This variant has been shown to have no deleterious effect on mismatch repair activity (PMID: 32849802 (2020)). The frequency of this variant in the general population, 0.00014 (5/35438 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
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.
Sema4, Sema4	RCV000131299	SCV002528625	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411981	SCV004018102	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003952686	SCV004771582	uncertain significance	MLH1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	The MLH1 c.1136A>G variant is predicted to result in the amino acid substitution p.Tyr379Cys. This variant has been reported in individuals with colorectal and ovarian cancer, and an asbestos-exposed patient with malignant pleural mesothelioma; although no evidence was provided to determine its pathogenicity (Taylor et al. 2003. PubMed ID: 14635101; Pal et al. 2012. PubMed ID: 23047549; Betti ett al. 2017. PubMed ID: 28687356). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and is interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142276/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000781987	SCV004840960	uncertain significance	Lynch syndrome	2023-11-30	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 breast/ovarian cancer (PMID: 26898890), ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 14635101, 21404117), melanoma (25148578), sarcoma (PMID: 27498913), and mesothelioma (PMID: 28687356). This variant has also been reported in individuals whose phenotypes suggest that this variant is not likely to be 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.