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NM_000179.3(MSH6):c.3477del (p.Cys1158_Tyr1159insTer) AND Hereditary nonpolyposis colon cancer

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 3, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001194391.1

Allele description [Variation Report for NM_000179.3(MSH6):c.3477del (p.Cys1158_Tyr1159insTer)]

NM_000179.3(MSH6):c.3477del (p.Cys1158_Tyr1159insTer)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3477del (p.Cys1158_Tyr1159insTer)
HGVS:
  • NC_000002.12:g.47804948del
  • NG_007111.1:g.26802del
  • NG_008397.1:g.105728del
  • NM_000179.3:c.3477delMANE SELECT
  • NM_001281492.2:c.3087del
  • NM_001281493.2:c.2571del
  • NM_001281494.2:c.2571del
  • NP_000170.1:p.Cys1158_Tyr1159insTer
  • NP_000170.1:p.Cys1158_Tyr1159insTer
  • NP_001268421.1:p.Cys1028_Tyr1029insTer
  • NP_001268422.1:p.Cys856_Tyr857insTer
  • NP_001268423.1:p.Cys856_Tyr857insTer
  • LRG_219t1:c.3477del
  • LRG_219:g.26802del
  • LRG_219p1:p.Cys1158_Tyr1159insTer
  • NC_000002.11:g.48032087del
  • NM_000179.2:c.3477del
  • NM_000179.2:c.3477delC
Links:
dbSNP: rs1114167767
NCBI 1000 Genomes Browser:
rs1114167767
Molecular consequence:
  • NM_000179.3:c.3477del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001281492.2:c.3087del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001281493.2:c.2571del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001281494.2:c.2571del - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:
Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:
MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001363899Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Oct 3, 2019) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome.

van Lier MG, Leenen CH, Wagner A, Ramsoekh D, Dubbink HJ, van den Ouweland AM, Westenend PJ, de Graaf EJ, Wolters LM, Vrijland WW, Kuipers EJ, van Leerdam ME, Steyerberg EW, Dinjens WN; LIMO Study Group..

J Pathol. 2012 Apr;226(5):764-74. doi: 10.1002/path.3963. Epub 2012 Jan 17.

PubMed [citation]
PMID:
22081473

Cancer Susceptibility Genetic Testing in a High-Risk Cohort of Urban Ashkenazi Jewish Individuals.

Nielsen SM, De Simone LM, Olopade OI.

J Genet Couns. 2018 Dec;27(6):1405-1410. doi: 10.1007/s10897-018-0269-x. Epub 2018 Jun 26.

PubMed [citation]
PMID:
29946849
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363899.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: MSH6 c.3477delC (p.Tyr1159X) 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.3514dupA (p.Arg1172fsX5), c.3991C>T (p.Arg1331X)). The variant was absent in 251396 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with colorectal cancer, endometrium cancer and pancreatic cancer (e.g. vanLier_2012, Yablonski-Peretz_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other variants with a different nucleotide change (c.3477C>A and c.3477C>G) resulting in same truncation (p.Tyr1159X) have been reported as pathogenic/likely pathogenic by us and others in ClinVar. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Oct 8, 2024