ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1681G>A (p.Glu561Lys) (rs63750328)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524354 SCV000284120 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 561 of the MSH2 protein (p.Glu561Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs63750328, ExAC 0.003%). This variant has been reported in an individual from a family affected with Lynch syndrome (PMID: 16395668), and in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 90745). This variant has been reported not to substantially affect MSH2 protein function (PMID: 30998989). 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.
Counsyl RCV000410128 SCV000487855 uncertain significance Lynch syndrome I 2015-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000484663 SCV000567206 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1681G>A at the cDNA level, p.Glu561Lys (E561K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in at least one individual with a personal and/or family history suspicious for Lynch syndrome, and an RT-PCR assay using this individual's RNA did not reveal any defect in splicing (Auclair 2006). MSH2 Glu561Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Glu561Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568086 SCV000669724 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing The p.E561K variant (also known as c.1681G>A), located in coding exon 11 of the MSH2 gene, results from a G to A substitution at nucleotide position 1681. The glutamic acid at codon 561 is replaced by lysine, an amino acid with similar properties. This variant was detected in an HNPCC family and did not cause any detectable effect on normal splicing (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color RCV000568086 SCV000690015 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000568086 SCV000822046 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198848 SCV001369843 uncertain significance Turcot syndrome 2018-10-05 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1.
Division of Medical Genetics, University of Washington RCV000410128 SCV001424806 uncertain significance Lynch syndrome I 2019-06-27 criteria provided, single submitter clinical testing The c.1681G>A variant has been reported in the literature in an individual from a family with Lynch syndrome (Auclair 2006). The c.1681G>A variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.

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