ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.301_306del (p.Glu101_Val102del) (rs587779157)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076562 SCV000107590 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics RCV000129228 SCV000183982 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing The c.301_306delGAAGTT variant is located in coding exon 2 of the MSH2 gene. This variant results from an in-frame six base pair deletion between nucleotide positions 301 and 306. This results in the deletion of a glutamic acid residue and a valine residue, two highly conserved amino acids, between codons 101 and 102. This alteration has been previously reported in multiple families that met Amsterdam and/or Bethesda criteria and included family members with colon tumors that demonstrated absent MSH2 staining on immunohistochemistry and high microsatellite instability (MSI-H) in known carriers of this variant (Glasl et al. Hum Mutat. 2000 Jul;16(1):91-2; Goldberg et al. Fam Cancer. 2008;7(4):309-17). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Of note, this variant is also referred to as 300-305delAGTTGA and c.297_302delAGTTGA in published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000236396 SCV000292865 likely pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing This deletion of 6 nucleotides in MSH2 is denoted c.301_306delGAAGTT at the cDNA level and p.E101_V102del at the protein level. This deletion is also known as MSH2 c.297_302delAGTTGA or 300_305delAGTTGA using alternate nomenclature. The normal sequence, with the bases that are deleted in braces, is AGTT[GAAGTT]TATA. This in frame deletion occurs in a region which is conserved across species and is located within the mismatch binding domain (Lutzen 2008). This variant was observed in at least two patients with early onset colorectal cancer meeting Lynch criteria with tumor studies demonstrating microsatellite instability and immunohistochemistry absent for MSH2 protein (Glasl 2000, Goldberg 2008). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). Based on the currently available information, we consider MSH2 p.Glu101_Val102del to be a likely pathogenic variant.
Counsyl RCV000409469 SCV000489343 likely pathogenic Lynch syndrome I 2016-09-21 criteria provided, single submitter clinical testing
Invitae RCV000791449 SCV000548187 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-25 criteria provided, single submitter clinical testing This sequence change deletes 6 nucleotides from exon 2 of the MSH2 mRNA (c.301_306delGAAGTT). This leads to the deletion of 2 amino acid residues in the MSH2 protein (p.Glu101_Val102del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with clinical features of Lynch syndrome (PMID: 10874318, 11179758, 18389388). This variant is also known as 300-305delAGTTGA, 300delAGTTGA, c.297_302delAGTTGA in the literature. ClinVar contains an entry for this variant (Variation ID: 91060). Based on a multifactorial likelihood algorithm using genetic and clinical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816), but this prediction has not been confirmed by published functional 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000076562 SCV000696259 likely pathogenic Lynch syndrome 2019-04-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.301_306delGAAGTT (p.Glu101_Val102del) results in an in-frame deletion that is predicted to remove 2 amino acids from the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein. The variant was absent in 251332 control chromosomes (gnomAD). c.301_306delGAAGTT has been reported in the literature in individuals affected with Lynch Syndrome (Latham_2019, Espenschied_2017, Goldberg_2008, Glasl_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) through multifactorial analysis classified the variant as likely pathogenic (Thompson_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), likely pathogenic (n=3) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000076562 SCV000788237 pathogenic Lynch syndrome 2018-04-01 criteria provided, single submitter research The MSH2 variant designated as NM_000251.2:c.301_306del is classified as likely pathogenic. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.99 to 1 (Thompson, et al., 2003, PMID:1290079), which provides some evidence that this allele is pathogenic. Multifactorial likelihood analysis from the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database gives a 95% probability of pathogenicity for this variant as of the year 2016 ( This variant is not found in the ExAC ( or gnomAD ( population databases or the UMD database ( This genomic region is highly conserved across species. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a >99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH2 function and increase cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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