ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1139T>C (p.Leu380Ser) (rs730881755)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160581 SCV000211173 uncertain significance not provided 2014-06-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1139T>C at the cDNA level, p.Leu380Ser (L380S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Leu380Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Leu380Ser occurs at a position that is well conserved across species and is located in the lever domain that interacts with MSH6 and MSH3 and stabilizes interaction with EXO1 (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Leu380Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000203771 SCV000261063 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 380 of the MSH2 protein (p.Leu380Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182557). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000215764 SCV000275173 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000780458 SCV000917725 uncertain significance not specified 2018-12-21 criteria provided, single submitter clinical testing Variant summary: The variant, MSH2 c.1139T>C (p.Leu380Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246242 control chromosomes (gnomAD). 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.1139T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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