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NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 10, 2023
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:
RCV000700703.9

Allele description [Variation Report for NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)]

NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)
HGVS:
  • NC_000002.12:g.47806464_47806477dup
  • NG_007111.1:g.28318_28331dup
  • NG_008397.1:g.104200_104213dup
  • NM_000179.3:c.3814_3827dupMANE SELECT
  • NM_001281492.2:c.3424_3437dup
  • NM_001281493.2:c.2908_2921dup
  • NM_001281494.2:c.2908_2921dup
  • NP_000170.1:p.Asp1277fs
  • NP_000170.1:p.Asp1277fs
  • NP_001268421.1:p.Asp1147fs
  • NP_001268422.1:p.Asp975fs
  • NP_001268423.1:p.Asp975fs
  • LRG_219t1:c.3814_3827dup
  • LRG_219:g.28318_28331dup
  • LRG_219p1:p.Asp1277fs
  • NC_000002.11:g.48033601_48033602insAGAAAATGAATGTG
  • NC_000002.11:g.48033603_48033616dup
  • NM_000179.2:c.3814_3827dup
  • NM_000179.2:c.3814_3827dupGAAAATGAATGTGA
Protein change:
D1147fs
Links:
dbSNP: rs1558393070
NCBI 1000 Genomes Browser:
rs1558393070
Molecular consequence:
  • NM_000179.3:c.3814_3827dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281492.2:c.3424_3437dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281493.2:c.2908_2921dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001281494.2:c.2908_2921dup - 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
SCV000829470Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 10, 2023)
germlineclinical testing

PubMed (5)
[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

MSH6 germline mutations are rare in colorectal cancer families.

Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA.

Int J Cancer. 2003 Nov 20;107(4):571-9.

PubMed [citation]
PMID:
14520694

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.

Goldberg Y, Porat RM, Kedar I, Shochat C, Galinsky D, Hamburger T, Hubert A, Strul H, Kariiv R, Ben-Avi L, Savion M, Pikarsky E, Abeliovich D, Bercovich D, Lerer I, Peretz T.

Fam Cancer. 2010 Jun;9(2):141-50. doi: 10.1007/s10689-009-9298-9.

PubMed [citation]
PMID:
19851887
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829470.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Asp1277Lysfs*55) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 577852). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 21155762, 24440087). 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 8, 2024