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NM_000179.3(MSH6):c.3935_3954dup (p.Lys1319fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 20, 2017
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:
RCV000543375.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3935_3954dup (p.Lys1319fs)]

NM_000179.3(MSH6):c.3935_3954dup (p.Lys1319fs)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3935_3954dup (p.Lys1319fs)
HGVS:
  • NC_000002.12:g.47806585_47806604dup
  • NG_007111.1:g.28439_28458dup
  • NG_008397.1:g.104072_104091dup
  • NM_000179.3:c.3935_3954dupMANE SELECT
  • NM_001281492.2:c.3545_3564dup
  • NM_001281493.2:c.3029_3048dup
  • NM_001281494.2:c.3029_3048dup
  • NP_000170.1:p.Lys1319fs
  • NP_001268421.1:p.Lys1189fs
  • NP_001268422.1:p.Lys1017fs
  • NP_001268423.1:p.Lys1017fs
  • LRG_219:g.28439_28458dup
  • NC_000002.11:g.48033723_48033724insTTATTCAAAAGGGACATAGA
  • NC_000002.11:g.48033724_48033743dup
  • NM_000179.2:c.3935_3954dupTTATTCAAAAGGGACATAGA
Protein change:
K1017fs
Links:
dbSNP: rs1553333644
NCBI 1000 Genomes Browser:
rs1553333644
Molecular consequence:
  • NM_000179.3:c.3935_3954dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281492.2:c.3545_3564dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281493.2:c.3029_3048dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281494.2:c.3029_3048dup - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000624946Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 20, 2017)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.

Raskin L, Schwenter F, Freytsis M, Tischkowitz M, Wong N, Chong G, Narod SA, Levine DA, Bogomolniy F, Aronson M, Thibodeau SN, Hunt KS, Rennert G, Gallinger S, Gruber SB, Foulkes WD.

Clin Genet. 2011 Jun;79(6):512-22. doi: 10.1111/j.1399-0004.2010.01594.x. Epub 2010 Dec 14.

PubMed [citation]
PMID:
21155762
PMCID:
PMC4541773

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]
PMID:
17531815
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000624946.4

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

Description

Two similar MSH6 variants, c.3959_3962delCAAG (p.Ala1320Glufs*6) and c.3984_3987dupGTCA (p.Leu1330Valfs*12), have been reported as Ashkenazi Jewish founder mutations known to cause Lynch syndrome (PMID: 21155762). This variant is not expected to result in nonsense-mediated decay, but it is expected to disrupt amino acid residues Lys1319-Leu1360 of the MSH6 protein. Although no functional studies have been performed to test the effects of this particular variant on MSH6 protein function or stability, it is expected to delete the C-terminal portion of the conserved MutS domain (PMID: 17531815, 24100870). This domain is necessary for the heterodimerization of MSH6 and MSH2 (PMID: 15952900, 16464007). This variant has not been reported in the literature in individuals with an MSH6-related disease. This sequence change inserts 20 nucleotides in exon 9 of the MSH6 mRNA (c.3935_3954dup20), causing a frameshift at codon 1319. This creates a premature translational stop signal in the penultimate exon of the MSH6 mRNA (p.Lys1319Leufs*15). While this is not anticipated to result in nonsense-mediated decay, it is expected to disrupt the last 42 amino acids of the MSH6 protein. 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: Sep 29, 2024