ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2362A>C (p.Thr788Pro) (rs774440277)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000585967 SCV000292626 uncertain significance not provided 2017-06-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2362A>C at the cDNA level, p.Thr788Pro (T788P) at the protein level, and results in the change of a Threonine to a Proline (ACT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr788Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr788Pro occurs at a position that is conserved across species and is located within the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Thr788Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000456146 SCV000548216 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 788 of the MSH2 protein (p.Thr788Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs774440277, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 245647). 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 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 RCV000569234 SCV000669733 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000569234 SCV000685037 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585967 SCV000696247 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2362A>C (p.Thr788Pro) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121390 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585967 SCV001152283 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing

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