ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2211-1G>T (rs267607979)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076430 SCV000107459 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000490951 SCV000580462 pathogenic Hereditary cancer-predisposing syndrome 2018-03-08 criteria provided, single submitter clinical testing Result Def in combination w/ c.1915C>T The c.1915C>T alteration (also known as p.H639Y), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1915. The histidine at codon 639 is replaced by tyrosine, an amino acid with similar properties. The c.2211-1G>T intronic alteration, results from a G to T one nucleotide upstream from coding exon 14 of the MSH2 gene. In one study, c.2211-1G>T was detected in cis with c.1915C>T, and this complex double mutation caused an in frame deletion of exons 12-14 in a patient diagnosed with colon cancer before 30 years of age. This result also correlated with short fragments detected by in vitro synthesized-protein–truncation assay. This individual's cancer was noted to exhibit microsatellite instability on tumor studies (Farrington et al. Am J Hum Genet. 1998 Sep; 63(3): 749-59). Based on the available evidence, the c.1915C>T+ c.2211-1G>T haplotype is classified as pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000076430 SCV000887425 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2211-1G>T has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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