ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.913G>A (p.Ala305Thr) (rs63751454)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656876 SCV000149456 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.913G>A at the cDNA level, p.Ala305Thr (A305T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was observed in at least three patients suspected of having Lynch syndrome, but a tumor from one of these individuals demonstrated low microsatellite instability and normal MSH2 protein expression (Wijnen 1997, Arnold 2009, Thompson 2013). MSH2 Ala305Thr demonstrated normal mismatch repair activity, binding, and cellular localization; however, the authors that performed these functional analyses were hesitant to call this variant neutral (Lutzen 2008, Drost 2011). The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence. MSH2 Ala305Thr was observed at an allele frequency of 0.012% (13/110,622) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ala305Thr is located in the Lever domain (L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ala305Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115547 SCV000213040 likely benign Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification;Intact protein function observed in appropriate functional assay(s)
Invitae RCV000656876 SCV000254431 likely benign not provided 2019-02-20 criteria provided, single submitter clinical testing
Color RCV000115547 SCV000537524 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656876 SCV000601493 uncertain significance not provided 2019-07-04 criteria provided, single submitter clinical testing
Mendelics RCV000076748 SCV000837823 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000986655 SCV001135710 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148633 SCV000190348 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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