ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1661+5G>C (rs267607972)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000490916 SCV000580545 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-09 criteria provided, single submitter clinical testing The c.1661+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 10 in the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in a Polish Lynch syndrome family and was shown to cause skipping of exon 10 leading to the creation of a new stop codon (Kurzawski G et al. J. Med. Genet., 2002 Oct;39:E65). This alteration has also been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835) and in an individual with endometrial cancer whose tumor showed microsatellite instability and loss of MSH2 protein staining via immunohistochemisty (Ferguson SE et al. Cancer, 2014 Dec;120:3932-9). In addition, this allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076218 SCV000592511 pathogenic Lynch syndrome 2016-08-17 criteria provided, single submitter clinical testing
Invitae RCV000812895 SCV000953225 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-22 criteria provided, single submitter clinical testing This sequence change falls in intron 10 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 (rs267607972, ExAC 0.001%). This variant has been observed in individuals affected with Lynch syndrome-related cancer (PMID: 12362047, 25081409, 27601186). ClinVar contains an entry for this variant (Variation ID: 90721). 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 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.

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