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NM_000179.3(MSH6):c.3934_3937dup (p.Ile1313fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 17, 2024
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:
RCV000629708.9

Allele description [Variation Report for NM_000179.3(MSH6):c.3934_3937dup (p.Ile1313fs)]

NM_000179.3(MSH6):c.3934_3937dup (p.Ile1313fs)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3934_3937dup (p.Ile1313fs)
Other names:
p.Ile1313SerfsX7
HGVS:
  • NC_000002.11:g.48033721_48033722insAGTT
  • NC_000002.12:g.47806584_47806587dup
  • NG_007111.1:g.28438_28441dup
  • NG_008397.1:g.104090_104093dup
  • NM_000179.3:c.3934_3937dupMANE SELECT
  • NM_001281492.2:c.3544_3547dup
  • NM_001281493.2:c.3028_3031dup
  • NM_001281494.2:c.3028_3031dup
  • NP_000170.1:p.Ile1313fs
  • NP_001268421.1:p.Ile1183fs
  • NP_001268422.1:p.Ile1011fs
  • NP_001268423.1:p.Ile1011fs
  • LRG_219t1:c.3934_3937dup
  • LRG_219:g.28438_28441dup
  • NC_000002.11:g.48033721_48033722insAGTT
  • NC_000002.11:g.48033723_48033726dup
  • NC_000002.11:g.48033726_48033727insGTTA
  • NM_000179.2:c.3934_3937dup
  • NM_000179.2:c.3934_3937dupGTTA
  • p.Ile1313Serfs*7
Protein change:
I1011fs
Links:
dbSNP: rs760190301
NCBI 1000 Genomes Browser:
rs760190301
Molecular consequence:
  • NM_000179.3:c.3934_3937dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281492.2:c.3544_3547dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281493.2:c.3028_3031dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281494.2:c.3028_3031dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000750664Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 17, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]
PMID:
25980754
PMCID:
PMC4550537

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]
PMID:
26681312
PMCID:
PMC4985612
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000750664.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Ile1313Serfs*7) in the MSH6 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome, family history of Lynch syndrome-associated cancers, and/or personal history of Lynch syndrome-associated cancers (PMID: 25980754, 26681312, 28369758). ClinVar contains an entry for this variant (Variation ID: 418610). Studies have shown that this premature translational stop signal results in skipping of exon 9 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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: Oct 20, 2024