NM_000179.3(MSH6):c.675dup (p.Glu226Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 29, 2022
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:: RCV002866787.3

Allele description [Variation Report for NM_000179.3(MSH6):c.675dup (p.Glu226Ter)]

NM_000179.3(MSH6):c.675dup (p.Glu226Ter)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.675dup (p.Glu226Ter)

HGVS:

NC_000002.12:g.47798658dup
NG_007111.1:g.20512dup
NM_000179.3:c.675dupMANE SELECT
NM_001281492.2:c.285dup
NM_001281493.2:c.-232dup
NM_001281494.2:c.-232dup
NM_001406795.1:c.771dup
NM_001406796.1:c.675dup
NM_001406797.1:c.378dup
NM_001406798.1:c.675dup
NM_001406799.1:c.150dup
NM_001406800.1:c.675dup
NM_001406801.1:c.378dup
NM_001406802.1:c.771dup
NM_001406803.1:c.675dup
NM_001406804.1:c.597dup
NM_001406805.1:c.378dup
NM_001406806.1:c.150dup
NM_001406807.1:c.150dup
NM_001406808.1:c.675dup
NM_001406809.1:c.675dup
NM_001406811.1:c.-232dup
NM_001406812.1:c.-232dup
NM_001406813.1:c.681dup
NM_001406814.1:c.-232dup
NM_001406815.1:c.-232dup
NM_001406816.1:c.-232dup
NM_001406817.1:c.675dup
NM_001406818.1:c.378dup
NM_001406819.1:c.378dup
NM_001406820.1:c.378dup
NM_001406821.1:c.378dup
NM_001406822.1:c.378dup
NM_001406823.1:c.-232dup
NM_001406824.1:c.378dup
NM_001406825.1:c.378dup
NM_001406826.1:c.507dup
NM_001406827.1:c.378dup
NM_001406828.1:c.378dup
NM_001406829.1:c.-232dup
NM_001406830.1:c.378dup
NP_000170.1:p.Glu226Ter
NP_000170.1:p.Glu226Terfs
NP_001268421.1:p.Glu96Ter
NP_001393724.1:p.Glu258Terfs
NP_001393725.1:p.Glu226Terfs
NP_001393726.1:p.Glu127Terfs
NP_001393727.1:p.Glu226Terfs
NP_001393728.1:p.Glu51Terfs
NP_001393729.1:p.Glu226Terfs
NP_001393730.1:p.Glu127Terfs
NP_001393731.1:p.Glu258Terfs
NP_001393732.1:p.Glu226Terfs
NP_001393733.1:p.Glu200Terfs
NP_001393734.1:p.Glu127Terfs
NP_001393735.1:p.Glu51Terfs
NP_001393736.1:p.Glu51Terfs
NP_001393737.1:p.Glu226Terfs
NP_001393738.1:p.Glu226Terfs
NP_001393742.1:p.Glu228Terfs
NP_001393746.1:p.Glu226Terfs
NP_001393747.1:p.Glu127Terfs
NP_001393748.1:p.Glu127Terfs
NP_001393749.1:p.Glu127Terfs
NP_001393750.1:p.Glu127Terfs
NP_001393751.1:p.Glu127Terfs
NP_001393753.1:p.Glu127Terfs
NP_001393754.1:p.Glu127Terfs
NP_001393755.1:p.Glu170Terfs
NP_001393756.1:p.Glu127Terfs
NP_001393757.1:p.Glu127Terfs
NP_001393759.1:p.Glu127Terfs
LRG_219t1:c.675dup
LRG_219:g.20512dup
LRG_219p1:p.Glu226Terfs
NC_000002.11:g.48025795_48025796insT
NC_000002.11:g.48025797dup
NM_000179.2:c.675dup
NR_176257.1:n.764dup
NR_176258.1:n.764dup
NR_176259.1:n.764dup
NR_176261.1:n.764dup

Protein change:

E226*

Molecular consequence:

NM_001281493.2:c.-232dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-232dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406795.1:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406796.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406797.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406798.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406799.1:c.150dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406800.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406801.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406802.1:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406803.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406804.1:c.597dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406805.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406806.1:c.150dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406807.1:c.150dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406808.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406809.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406813.1:c.681dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406817.1:c.675dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406818.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406819.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406820.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406821.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406822.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406824.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406825.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406826.1:c.507dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406827.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406828.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406830.1:c.378dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_000179.3:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.285dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406795.1:c.771dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406796.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406797.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406798.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406799.1:c.150dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406800.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406801.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406802.1:c.771dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406803.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406804.1:c.597dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406805.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406806.1:c.150dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406807.1:c.150dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406808.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406809.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406813.1:c.681dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406817.1:c.675dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406818.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406819.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406820.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406821.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406822.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406824.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406825.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406826.1:c.507dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406827.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406828.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001406830.1:c.378dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003233541	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18269114, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003233541

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 29, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.

Devlin LA, Graham CA, Price JH, Morrison PJ.

Ulster Med J. 2008 Jan;77(1):25-30.

PubMed [citation]

PMID:: 18269114
PMCID:: PMC2397009

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]

PMID:: 24362816
PMCID:: PMC4294709

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003233541.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu226*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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