ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524340 SCV000254382 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-11 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). This variant has been reported not to substantially affect MSH2 protein function (PMID: 31237724). 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 Health, Inc RCV000446874 SCV000537566 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-04 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 441 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant rescued MSH2-deficient human embryonic stem cells (PMID: 31237724) and was partially active compared to wild-type in a 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells (internally defined score thresholds, PMID: 33357406). This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 16636019, 18383312, 23047549) for which tumors in two carriers showed MMR-proficient characteristics (PMID: 16636019, 18383312). This variant also has been reported in an individual affected with breast cancer (PMID: 25503501). This variant has been identified in 7/282308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV000478413 SCV000565189 uncertain significance not provided 2020-08-31 criteria provided, single submitter clinical testing Observed in individuals with colorectal, pancreatic, ovarian, and breast cancer (Niessen 2006, Chao 2008, Pal 2012, Maxwell 2015); Published functional studies demonstrate no damaging effect: only slightly reduced protein expression, normal sensitivity to DNA damage, and stable microsatellite instability analysis (Rath 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31237724, 26333163, 16636019, 23047549, 25503501, 18383312, 22290698)
Ambry Genetics RCV000446874 SCV000662229 likely benign Hereditary cancer-predisposing syndrome 2020-07-17 criteria provided, single submitter clinical testing Other data supporting benign classification
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001001300 SCV001737626 uncertain significance not specified 2021-05-21 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1321A>C (p.Thr441Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein mut S, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1321A>C has been reported in the literature in individuals affected with MSI-low colorectal cancer and one patient with positive IHC staining for MLH1 and MSH2 (Chao_2008, Niessen_2006), early onset breast cancer (Maxwell_2014), epithelial ovarian cancer (Pal_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on measures of protein stability, DNA repair function and damage response signaling in an experimental system using CRISPR Cas9 gene editing to engineer VUS in human embryonic cells (Rath_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=5). Some submitters, to include one classifying the variant as likely benign utilize overlapping functional and other evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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