ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1321G>A (p.Ala441Thr)

gnomAD frequency: 0.00034  dbSNP: rs63750365
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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075170 SCV000106161 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000679266 SCV000149365 likely benign not provided 2020-12-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16042583, 16438707, 20223024, 21056691, 25637381, 11524701, 19117025, 17510385, 10709098, 22949379, 11376800, 23741719, 15849733, 9326924, 24055113, 27153395, 26659639, 28526081, 21404117, 18383312, 29785566, 17192056, 32547938)
Ambry Genetics RCV000115456 SCV000184608 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Invitae RCV001083668 SCV000219061 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000202064 SCV000539641 uncertain significance not specified 2017-01-10 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: Two mammals and one non-mammal have a Thr at this position. It has a max MAF of 0.09% in gnomAD. It is reported in 7 papers in HGMD, classified as DM, most comments suggest VUS. It is classified in ClinVar with 3 stars as Benign by InSiGHT (expert panel) and Pathway genomics, and likely benign by GeneDx and Invitae, and as VUS by Mayo and CSER_CC_NCGL.
Genetic Services Laboratory, University of Chicago RCV000202064 SCV000595807 benign not specified 2021-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679266 SCV000601351 benign not provided 2022-11-11 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659870 SCV000781755 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2016-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000659870 SCV000786114 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2018-02-28 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000679266 SCV000805947 likely benign not provided 2017-04-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000679266 SCV000884118 benign not provided 2018-02-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115456 SCV000902604 benign Hereditary cancer-predisposing syndrome 2015-10-15 criteria provided, single submitter clinical testing
Mendelics RCV000659870 SCV001136408 benign Colorectal cancer, hereditary nonpolyposis, type 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000679266 SCV001153842 likely benign not provided 2023-11-01 criteria provided, single submitter clinical testing MLH1: BP4, BS3:Supporting
Illumina Laboratory Services, Illumina RCV000659870 SCV001308772 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2018-03-29 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202064 SCV001737682 benign not specified 2021-06-14 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1321G>A (p.Ala441Thr) 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 0.00034 in 251274 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00034 vs 0.00071), allowing no conclusion about variant significance. c.1321G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (example Borg_2000, Cunningham_2001, Mangold_2005, Kurzawski_2006, South_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and observed in our laboratory (Borg_2000, BRCA1 3166insTGAGA; our laboratory, MSH6 c.999delC, p.Lys334fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on mismatch repair activity (MMR). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus leaning towards benign/likely benign (n=11). Based on the overwhelming evidence supporting a non-actionable as outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798259 SCV002042072 likely benign Breast and/or ovarian cancer 2023-04-14 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115456 SCV002528638 benign Hereditary cancer-predisposing syndrome 2021-03-04 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000202064 SCV002760287 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115456 SCV002819232 benign Hereditary cancer-predisposing syndrome 2022-11-22 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000659870 SCV004018204 benign Colorectal cancer, hereditary nonpolyposis, type 2 2023-03-16 criteria provided, single submitter clinical testing This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Pathway Genomics RCV000144611 SCV000189938 benign Lynch syndrome 1 2014-07-24 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148618 SCV000190333 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000202064 SCV000257050 uncertain significance not specified no assertion criteria provided research
True Health Diagnostics RCV000115456 SCV000788017 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 no assertion criteria provided clinical testing

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