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

dbSNP: rs370687064

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085064	SCV000166243	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-22	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: 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.
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	2024-10-30	criteria provided, single submitter	clinical testing	The MLH1 c.1268G>A (p.Arg423Lys) variant has been reported in the published literature 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 reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000035 (4/113622 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.