NM_000251.3(MSH2):c.1360A>G (p.Ile454Val) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Oct 25, 2017)

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:
RCV000588274.1

Allele description [Variation Report for NM_000251.3(MSH2):c.1360A>G (p.Ile454Val)]

NM_000251.3(MSH2):c.1360A>G (p.Ile454Val)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.1360A>G (p.Ile454Val)
HGVS:
  • NC_000002.12:g.47445631A>G
  • NG_007110.2:g.47508A>G
  • NM_000251.2:c.1360A>G
  • NM_000251.3:c.1360A>GMANE SELECT
  • NM_001258281.1:c.1162A>G
  • NP_000242.1:p.Ile454Val
  • NP_000242.1:p.Ile454Val
  • NP_001245210.1:p.Ile388Val
  • LRG_218t1:c.1360A>G
  • LRG_218:g.47508A>G
  • LRG_218p1:p.Ile454Val
  • NC_000002.11:g.47672770A>G
  • NM_000251.1:c.1360A>G
  • p.I454V
Protein change:
I388V
Links:
dbSNP: rs587781627
NCBI 1000 Genomes Browser:
rs587781627
Molecular consequence:
  • NM_000251.2:c.1360A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000251.3:c.1360A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1162A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000565191GeneDxcriteria provided, single submitter
Uncertain significance
(Oct 25, 2017)
germlineclinical testing

Citation Link,

SCV000696208Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 20, 2017)
germlineclinical testing

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000565191.5

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

Description

This variant is denoted MSH2 c.1360A>G at the cDNA level, p.Ile454Val (I454V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile454Val was not observed at a significant frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile454Val occurs at a position that is conserved across species and is located in the lever domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ile454Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696208.1

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

Description

Variant summary: The MSH2 c.1360A>G (p.Ile454Val) variant causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 119816 control chromosomes. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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

Last Updated: Nov 27, 2021

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