NM_000251.2(MSH2):c.1705_1706delGA (p.Glu569Ilefs) AND Lynch syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 5, 2013)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000030243.3

Allele description [Variation Report for NM_000251.2(MSH2):c.1705_1706delGA (p.Glu569Ilefs)]

NM_000251.2(MSH2):c.1705_1706delGA (p.Glu569Ilefs)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.2(MSH2):c.1705_1706delGA (p.Glu569Ilefs)
HGVS:
  • NC_000002.12:g.47471008_47471009delGA
  • NG_007110.2:g.72885_72886delGA
  • NM_000251.2:c.1705_1706delGA
  • NM_001258281.1:c.1507_1508delGA
  • NP_000242.1:p.Glu569Ilefs
  • NP_001245210.1:p.Glu503Ilefs
  • LRG_218t1:c.1705_1706delGA
  • LRG_218:g.72885_72886delGA
  • LRG_218p1:p.Glu569Ilefs
  • NC_000002.11:g.47698147_47698148delGA
  • NM_000251.1:c.1705_1706del
  • NM_000251.1:c.1705_1706delGA
  • p.E569IfsX2
  • p.Glu569IlefsX2
Links:
dbSNP: 63750393
NCBI 1000 Genomes Browser:
rs63750393
Molecular consequence:
  • NM_000251.2:c.1705_1706delGA - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Lynch syndrome (HNPCC)
Synonyms:
Hereditary nonpolyposis colon cancer
Identifiers:
MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000052910LabCorpcriteria provided, single submitter
pathogenic
(Aug 18, 2011)
germlinecuration, clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV000107273InSiGHTreviewed by expert panel
Pathogenic
(Sep 5, 2013)
germlineresearch

Citation Link,

SCV000548247Invitaecriteria provided, single submitter
Pathogenic
(Oct 31, 2016)
germlineclinical testing

Citation Link

Description

SCV000107273

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes6not providednot provided6not providedliterature only
not providedgermlineunknown1not providednot providednot providednot providedclinical testing, research

Citations

PubMed

Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States.

Kurzawski G, Suchy J, Kładny J, Safranow K, Jakubowska A, Elsakov P, Kucinskas V, Gardovski J, Irmejs A, Sibul H, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Clark J, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, et al.

J Med Genet. 2002 Oct;39(10):E65. No abstract available.

PubMed [citation]
PMID:
12362047
PMCID:
PMC1734972

Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation.

Wagner A, Tops C, Wijnen JT, Zwinderman K, van der Meer C, Kets M, Niermeijer MF, Klijn JG, Tibben A, Vasen HF, Meijers-Heijboer H.

J Med Genet. 2002 Nov;39(11):833-7. No abstract available.

PubMed [citation]
PMID:
12414824
PMCID:
PMC1735004
See all PubMed Citations (12)

Details of each submission

From LabCorp, SCV000052910.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedcuration PubMed (12)
2not provided2not providednot providedcuration PubMed (12)
3not provided1not providednot providedcuration PubMed (12)
4not provided1not providednot providedcuration PubMed (12)
5not provided1not providednot providedcuration PubMed (12)
6not providednot providednot providednot providedclinical testing PubMed (12)

Description

"Variant was detected in a 32 y.o. male diagnosed with CRC meeting the Amsterdam criteria; authors suggest the variant is likely pathogenic; the tumor was examined (see aFXN); controls not tested."
"The variant was detected in Spanish family #64 who meet the Amsterdam clinical criteria; MSI is present in the family; there were 2 concordant affected individuals; the proband's daughter (III:6) was unaffected but just 44 years of age, so could possibly still manifest symptoms (thus not counted as discordant); controls not tested."
"The variant was detected in Spanish family #64 who meet the Amsterdam clinical criteria; MSI is present in the family; zygosity and frequency of the variant was not specified so at least 1 occurrence was counted; the authors list the variant as a pathogenic mutation; controls not tested."
"Variant was detected in a HNPCC family; frequency and zygosity was not reported; thus only one occurrence was counted; controls not tested."
"Variant was detected in a HNPCC patient that meets the Amsterdam criteria; zygosity was not specified, therefore only one occurrence was counted; controls not tested."
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes2not providednot provided2not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not providednot provided1not providednot providednot provided
5germlineyes1not providednot provided1not providednot providednot provided
6germlineunknownnot providedBloodassert pathogenicitynot providednot providednot provided See 6

Co-occurrences

#ZygosityAllelesNumber of Observations
6SingleHeterozygote1

From InSiGHT, SCV000107273.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided

Description

Coding sequence variation introducing premature termination codon

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

From Invitae, SCV000548247.1

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

Description

This sequence change deletes 2 nucleotides in exon 11 of the MSH2 mRNA (c.1705_1706delGA), causing a frameshift at codon 569. This creates a premature translational stop signal (p.Glu569Ilefs*2) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families with Lynch syndrome (PMID: 15713769, 15849733, 20587412, 19698169, 24278394, 11920650, 15655560). This variant has also been reported in individuals with breast cancer (PMID: 16311127, 20215533) and an individual with prostate cancer and a family history of colorectal, duodenal and prostate cancer (PMID: 20872076). This variant is also known as c.1704_1705delAG. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jun 12, 2017