NM_000179.3(MSH6):c.3561_3565dup (p.Thr1189fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 17, 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:: RCV001873335.6

Allele description [Variation Report for NM_000179.3(MSH6):c.3561_3565dup (p.Thr1189fs)]

NM_000179.3(MSH6):c.3561_3565dup (p.Thr1189fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3561_3565dup (p.Thr1189fs)

HGVS:

NC_000002.12:g.47805622_47805626dup
NG_007111.1:g.27476_27480dup
NG_008397.1:g.105051_105055dup
NM_000179.3:c.3561_3565dupMANE SELECT
NM_001281492.2:c.3171_3175dup
NM_001281493.2:c.2655_2659dup
NM_001281494.2:c.2655_2659dup
NP_000170.1:p.Thr1189fs
NP_001268421.1:p.Thr1059fs
NP_001268422.1:p.Thr887fs
NP_001268423.1:p.Thr887fs
LRG_219t1:c.3561_3565dup
LRG_219:g.27476_27480dup
NC_000002.11:g.48032759_48032760insAAAGT
NC_000002.11:g.48032761_48032765dup
NM_000179.2:c.3561_3565dup
NM_000179.2:c.3561_3565dupAAGTA

Protein change:

T1059fs

Links:

dbSNP: rs891318615

NCBI 1000 Genomes Browser:

rs891318615

Molecular consequence:

NM_000179.3:c.3561_3565dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3171_3175dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2655_2659dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2655_2659dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002243769	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 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

SCV002243769

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 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, SCV002243769.4

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

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 823930). 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.Thr1189Lysfs*8) 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). For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 8, 2024

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