ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2211-10T>A (rs267608006)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000791387 SCV000260343 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-20 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Lynch syndrome (PMID: 17199584). ClinVar contains an entry for this variant (Variation ID: 90927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional 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.
GeneDx RCV000478566 SCV000569683 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2211-10T>A or IVS13-10T>A and consists of a T>A nucleotide substitution at the -10 position of intron 13 of the MSH2 gene. In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has been observed in at least one individual with a personal history of colorectal cancer, a sebaceous adenoma, melanoma, and prostate cancer, as well as a family history of colorectal cancer (Mangold 2007). Immunohistochemistry performed on a tumor from this individual revealed absence of the MSH2 and MSH6 proteins. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MSH2 c.2211-10T>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491555 SCV000580509 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-21 criteria provided, single submitter clinical testing ​The c.2211-10T>A intronic variant results from a T to A substitution 10 nucleotides before coding exon 14 in the MSH2 gene. This variant has been reported in a patient diagnosed with Muir-Torre syndrome whose personal history consisted of colorectal cancer at the age of 47 and prostate cancer, melanoma, and a sebaceous adenoma all at the age of 68. Tumor immunohistochemistry analysis (IHC) showed the absence of MSH2 and MSH6. The patient's family history of cancer consisted of a brother diagnosed with colorectal cancer at the age of 54, a father diagnosed with colorectal cancer at an unknown age, and a mother diagnosed with esophageal cancer at an unknown age (Mangold et al. Br J Dermatol. 2007 Jan;156(1):158-62). This alteration has also been detected in multiple individuals whose family history meets Amsterdam criteria and whose tumors showed absence of the MSH2 protein on IHC (Ambry internal data). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000491555 SCV000903947 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-03 criteria provided, single submitter clinical testing

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