ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1360G>C (p.Gly454Arg) (rs63750527)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587838 SCV000149367 likely benign not provided 2021-09-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30998989, 28874130, 25929848, 27150160, 12624141, 18383312, 22290698, 16395668, 25133505, 21404117, 31159747)
Invitae RCV001080105 SCV000166244 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115458 SCV000184486 likely benign Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing Other data supporting benign classification;Structural Evidence
Counsyl RCV000410484 SCV000487861 uncertain significance Lynch syndrome II 2015-11-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000200984 SCV000539644 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 6/16506 South Asian; ClinVar: 4 VUS (1 expert panel)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587838 SCV000601352 likely benign not provided 2019-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200984 SCV000696108 likely benign not specified 2020-12-03 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1360G>C (p.Gly454Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250988 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00012 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1360G>C, has been reported in the literature in individuals affected with tumors that belong to the Lynch syndrome tumor spectrum (e.g. Parc_2003, Auclair_2006, Hardt_2011, Loizidou_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported (MSH2 c.1165C>T (p.Arg389X) in UMD; and BRCA1 c.3700_3704delGTAAA (p.Val1234fsX8), CHEK2 c.1169A>C (p.Tyr390Ser), MSH2 c.2006-2A>T in internal LCA samples), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant (Bouvet_2019). 13 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (9x) or likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000115458 SCV000822020 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000075179 SCV000838014 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587838 SCV000885705 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing The MLH1 c.1360G>C;p.Gly454Arg is reported in the medical literature in individuals with Lynch syndrome (Auclair 2006, Lucci-Cordisco 2006, Loizidou 2014, and Hardt 2011). multiple computational analyses indicate the variant has a neutral effect on the MLH1 protein (Chao 2008). This variant is listed in the dbSNP variant database (rs63750527) and in the Genome Aggregation Database in 28 individuals (28 out of 277032 alleles). The p.Gly454Arg variant is classified by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) as a variant of uncertain significance because there is insufficient evidence about this variant (Variation ID: 89705). The glycine at this position is weakly conserved across species and computational algorithms (AlignGVGD, Polyphen2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Chao et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat. 2008; 29(6):852-860. Hardt et al. Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. Fam Cancer. 2011;10(2):273-284. Loizidou et al. The mutational spectrum of Lynch syndrome in cyprus. PLoS One. 2014; 9(8):e105501. Lucci-Cordisco et al. The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome. Cancer Biomark. 2006;2(1-2):11-27.
Fulgent Genetics,Fulgent Genetics RCV000764492 SCV000895563 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115458 SCV000902779 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Mendelics RCV000410484 SCV001136410 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587838 SCV001153843 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410484 SCV001308773 uncertain significance Lynch syndrome II 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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