ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1862G>T (p.Arg621Leu) (rs759263820)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491320 SCV000580563 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000491320 SCV000690024 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
GeneDx RCV000656880 SCV000292624 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1862G>T at the cDNA level, p.Arg621Leu (R621L) at the protein level, and results in the change of an Arginine to a Leucine (CGA>CTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg621Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg621Leu occurs at a position that is conserved across species and is located in the ATPase domain and in the region of interaction with EXO1 (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Arg621Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000201977 SCV000917704 uncertain significance not specified 2018-06-08 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1862G>T (p.Arg621Leu) results in a non-conservative amino acid change in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 30938 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1862G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported in our internal database (MSH6 c.3699_3702delAGAA, p.Lys1233fsX6). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000205853 SCV000261128 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 621 of the MSH2 protein (p.Arg621Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 218040). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201977 SCV000257155 uncertain significance not specified no assertion criteria provided research

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