NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs) AND Lynch syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 21, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs)]

NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs)

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs)
  • NC_000002.12:g.47429916_47429933delinsAGTT
  • NG_007110.2:g.31793_31810delinsAGTT
  • NM_000251.3:c.1251_1268delinsAGTTMANE SELECT
  • NM_001258281.1:c.1053_1070delinsAGTT
  • NP_000242.1:p.Ile418fs
  • NP_001245210.1:p.Ile352fs
  • LRG_218:g.31793_31810delinsAGTT
  • NC_000002.11:g.47657055_47657072delinsAGTT
  • NM_000251.1:c.1251_1268del18insAGTT
  • p.Ile418ValfsX3
Protein change:
dbSNP: rs863225388
NCBI 1000 Genomes Browser:


Lynch syndrome
Familial nonpolyposis colon cancer
MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000712553Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
(Nov 18, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000919709Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jun 21, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing



A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000712553.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)


The p.Ile418Valfs variant in MSH2 has not been previously reported in individual s with Lynch Syndrome or in large population studies, though the ability of thes e studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 418 and leads to a premature termination codon 3 amino acids downstr eam. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechan ism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manne r based upon the predicted impact to the protein.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919709.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


Variant summary: MSH2 c.1251_1268delinsAGTT (p.Ile418ValfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1477C>T, p.Gln493X; c.1576delA, p.Thr526fsX17; c.1705_1706delGA, p.Glu569fsX2). The variant was absent in 246126 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1251_1268delinsAGTT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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