ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1321A>C (p.Thr441Pro) (rs587779086)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524340 SCV000254382 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 441 of the MSH2 protein (p.Thr441Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs587779086, ExAC 0.005%). This variant has been reported in individuals affected with breast, ovarian and colon cancer (PMID: 25503501, 23047549, 18383312). ClinVar contains an entry for this variant (Variation ID: 90628). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH2 gene (PMID: 22290698), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.
Color RCV000446874 SCV000537566 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000478413 SCV000565189 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1321A>C at the cDNA level, p.Thr441Pro (T441P) at the protein level, and results in the change of a Threonine to a Proline (ACT>CCT). This variant has been observed in individuals with colorectal, pancreatic, ovarian, and breast cancer (Niessen 2006, Chao 2008, Pal 2012, Maxwell 2015). The International Society for Gastrointestinal Hereditary Tumors Incorporated (InSiGHT) classifies this variant as having uncertain clinical significance (Thompson 2014). MSH2 Thr441Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain and the region of interaction with MSH6 and MSH3 (Guerette 1998, L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Thr441Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000446874 SCV000662229 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001300 SCV001158480 uncertain significance not specified 2019-05-15 criteria provided, single submitter clinical testing The MSH2 c.1321A>C; p.Thr441Pro variant (rs587779086) is reported in the literature in multiple individuals affected with colorectal, ovarian, and breast cancer (Chao 2008, Maxwell 2015, Pal 2012). This variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 90628), and is found in the non-Finnish European population with an allele frequency of 0.005% (7/128884 alleles) in the Genome Aggregation Database. The threonine at codon 441 is weakly conserved, and computational analyses (Ali 2012, SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Thr441Pro variant is uncertain at this time. References Ali H et al. Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat. 2012 Apr;33(4):642-50. Chao EC et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat. 2008 Jun;29(6):852-60. Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90.
Illumina Clinical Services Laboratory,Illumina RCV001143792 SCV001304347 uncertain significance Lynch syndrome I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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