NM_000179.2(MSH6):c.3991C>T (p.Arg1331Ter) AND Lynch syndrome

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

Review status:(3/4)3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000035325.2

Allele description [Variation Report for NM_000179.2(MSH6):c.3991C>T (p.Arg1331Ter)]

Gene:
MSH6:mutS homolog 6 [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.3991C>T (p.Arg1331Ter)
HGVS:
  • NC_000002.12:g.47806641C>T
  • NG_007111.1:g.28495C>T
  • NG_008397.1:g.104035G>A
  • NM_000179.2:c.3991C>T
  • NM_025133.4:c.*1477G>A
  • NP_000170.1:p.Arg1331Ter
  • LRG_219t1:c.3991C>T
  • LRG_219:g.28495C>T
  • LRG_219p1:p.Arg1331Ter
  • NC_000002.11:g.48033780C>T
  • c.3991C>T
  • p.R1331*
Protein change:
R1331*
Links:
dbSNP: 267608094
NCBI 1000 Genomes Browser:
rs267608094
Molecular consequence:
  • NM_025133.4:c.*1477G>A - 500B downstream variant - [Sequence Ontology: SO:0001634]
  • NM_000179.2:c.3991C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Lynch syndrome (HNPCC)
Synonyms:
Hereditary nonpolyposis colon cancer; Hereditary non-polyposis colon cancer; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:
MedGen: C0009405

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Assertion and evidence details

Submission AccessionSubmitterReview StatusClinical Significance
(Last evaluated)
OriginMethodConsequenceCitations
SCV000108181InSiGHTreviewed by expert panelPathogenic
(Sep 5, 2013)
germlineresearch

Citation Link,

SCV000058973Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicineclassified by single submitterprobably pathogenic
(Dec 3, 2012)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Description

SCV000108181

Summary from all submissions

EthnicityOriginAffectedAlleles observedFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot provided1not providednot providednot providedclinical testing

Citations

PubMed

Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.

Plaschke J, Linnebacher M, Kloor M, Gebert J, Cremer FW, Tinschert S, Aust DE, von Knebel Doeberitz M, Schackert HK.

Eur J Hum Genet. 2006 May;14(5):561-6.

PubMed [citation]
PMID:
16418736

Comprehensive molecular characterization of human colon and rectal cancer.

Cancer Genome Atlas Network.

Nature. 2012 Jul 18;487(7407):330-7. doi: 10.1038/nature11252.

PubMed [citation]
PMID:
22810696
PMCID:
PMC3401966
See all PubMed Citations (4)

Details of each submission

From InSiGHT, SCV000108181.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided

Description

Coding sequence variation resulting in a stop codon (variant causes splicing aberration)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000058973.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The Arg1331X variant in MSH6 has been reported in at least 2 individuals with HNPCC related tumors (Plaschke 2006, Stormorken 2005). In one individual, the Arg1331X variant was present in compound heterozygosity with a second variant and presented with early onset presentation of disease (Plaschke 2006). Studies have shown that this variant produces a shorter transcript and results in reduced MSH6 protein expression in patient samples (Plaschke 2006). Heterozygous loss of function variants in MSH6 have been associated with predisposition to hereditary non-polyposis colorectal cancer and related cancers. In summary, this variant is likely pathogenic, though additional segregation and functional studies are required to fully establish its clinical significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providedassert pathogenicitynot providednot provided1not provided

Last Updated: Sep 12, 2014

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