NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 5, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000491837.2

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

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

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.1251_1268delinsAGTT (p.Ile418fs)
HGVS:
  • 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:
I352fs
Links:
dbSNP: rs863225388
NCBI 1000 Genomes Browser:
rs863225388
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000580484Ambry Geneticscriteria provided, single submitter
Pathogenic
(Mar 9, 2016)
germlineclinical testing

Citation Link,

SCV001736330Color Health, Inccriteria provided, single submitter
Pathogenic
(Oct 5, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000580484.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.1251_1268del18insAGTT pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from the deletion of 18 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV001736330.1

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

Description

This variant affects 18 nucleotides, causing a frameshift, in exon 7 of the MSH2 gene. The variant creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer and/or polyps (PMID: 31422818). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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

Last Updated: Dec 2, 2021

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