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
Invitae RCV000205853 SCV000261128 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-21 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 observed in several individuals with clinical features of Lynch syndrome (PMID: 30702970, Invitae). Also, it has been observed in multiple individuals affected with Lynch syndrome 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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.
Ambry Genetics RCV000491320 SCV000580563 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing 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 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000201977 SCV000917704 uncertain significance not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1862G>T (p.Arg621Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, 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 was absent in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1862G>T has been reported in the literature in an individual affected with Lynch Syndrome (Salvador_2019). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant has been reported (MSH6 c.3699_3702delAGAA, p.Lys1233fsX6), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201977 SCV000257155 uncertain significance not specified no assertion criteria provided research

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