ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1864C>A (p.Pro622Thr) (rs63750280)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491749 SCV000580567 uncertain significance Hereditary cancer-predisposing syndrome 2014-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000255200 SCV000322358 likely pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1864C>A at the cDNA level, p.Pro622Thr (P622T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). This variant was observed in at least one individual from with colorectal cancer as well as MSH2-absent bladder and ureter cancers (Skeldon 2013). This variant was also identified in an individual with colon cancer from a family meeting Amsterdam I criteria (Chialina 2006). In addition, a different variant at the same position, Pro622Leu, has been reported in individuals with Lynch syndrome and functional studies have demonstrated impaired function compared to wild type (Mastrocola 2010, Drost 2012, Thompson 2013).MSH2 Pro622Thr was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro622Thr occurs at a position that is conserved across species and is located in the ATPase domain and the region of interaction with EXO1 (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Pro622Thr to be a likely pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076306 SCV000107328 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence

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