ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.775C>T (p.Pro259Ser) (rs587781294)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128997 SCV000172892 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000128997 SCV000685129 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000759122 SCV000292619 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.775C>T at the cDNA level, p.Pro259Ser (P259S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant was observed in at least two families suspected of having Lynch Syndrome as well as at least one individual with a history of breast cancer (Bonadona 2011, Tung 2016). MSH2 Pro259Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro259Ser occurs at a position that is conserved in mammals and is located in the connector domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Pro259Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228319 SCV000284183 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 259 of the MSH2 protein (p.Pro259Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs587781294, ExAC 0.002%). This variant has been reported in individuals affected with Lynch syndrome (PMID: 21642682, 12624141), in at least one individual affected with breast cancer (PMID: 26976419), and an individual in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 140810). 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 tolerated, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235651 SCV000601489 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759122 SCV000888232 uncertain significance not provided 2018-07-04 criteria provided, single submitter clinical testing

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