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
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.
Ambry Genetics RCV000491749 SCV000580567 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Invitae RCV001036384 SCV001199745 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 622 of the MSH2 protein (p.Pro622Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families with Lynch syndrome (LS) or clinical features of LS (PMID: 16426447, 25117503, 29987844, 28874130, 22883484). ClinVar contains an entry for this variant (Variation ID: 90805). This variant has been reported to have conflicting or insufficient data to determine the effect on MSH2 protein function (PMID: 28422960). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). This variant disrupts the p.Pro622 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8261515, 16616355, 17720936, 21309037, 24362816, 22949379, 19267393). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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