ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1268G>A (p.Arg423Lys)

dbSNP: rs370687064
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085064 SCV000166243 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131167 SCV000186112 likely benign Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Counsyl RCV000411892 SCV000488386 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2016-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000588087 SCV000570384 likely benign not provided 2020-11-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21404117, 28767289)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588087 SCV000696102 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1268G>A (p.Arg423Lys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 4/121390 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). One reputable database (UMD) reported a patient carries the variant of interest and MLH1 c.676C>T (p.Arg226X, classified pathogenic in ClinVar), suggesting the variant of interest may not associate with the disease. In addition, multiple clinical diagnostic laboratories/reputable databases provided conflicting classifications: likely benign and VUS. Taken together, this variant is classified as VUS-possibly benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000487001 SCV000713006 uncertain significance not specified 2017-04-17 criteria provided, single submitter clinical testing The p.Arg423Lys variant in MLH1 has not been previously reported in individuals with Lynch syndrome, but has been reported in ClinVar (Variation ID 135846). Thi s variant has also been identified in 4/66720 of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3706870 64). Computational prediction tools and conservation analysis suggest that the p .Arg423Lys variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg423Lys variant is uncertain.
Color Diagnostics, LLC DBA Color Health RCV000131167 SCV000906463 benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000588087 SCV002009377 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000411892 SCV004018139 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2023-03-14 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].
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588087 SCV004220063 uncertain significance not provided 2023-01-31 criteria provided, single submitter clinical testing In the published literature, the variant has been reported in individuals with colon cancer (PMID: 21404117 (2011)) and pancreatic cancer (PMID: 28767289 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD http://databases.lovd.nl/shared/genes/MLH1)). The frequency of this variant in the general population, 0.000035 (4/113622 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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