ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.792+5A>G (rs267607935)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129148 SCV000183869 likely benign Hereditary cancer-predisposing syndrome 2017-05-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000129148 SCV000902909 likely benign Hereditary cancer-predisposing syndrome 2016-02-22 criteria provided, single submitter clinical testing
Counsyl RCV000410638 SCV000489026 uncertain significance Lynch syndrome I 2016-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000440249 SCV000513654 likely benign not specified 2017-08-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000589455 SCV000696283 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.792+5A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict the variant to result in the strengthening of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/119958 control chromosomes at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant was reported in an affected individual in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076710 SCV000107746 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524421 SCV000548228 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs267607935, ExAC 0.005%). This variant has been observed in an individual affected with colorectal adenomas (PMID: 15520370). This variant is also known as 795i+5A>G or IVS4+5A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 91206). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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.

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