Total submissions: 8
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 | |
Gene |
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 | |
Gene |
RCV000568086 | SCV000822046 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
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, |
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. |