NM_000179.3(MSH6):c.2238dup (p.Leu747fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 13, 2021
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:: RCV000558657.10

Allele description [Variation Report for NM_000179.3(MSH6):c.2238dup (p.Leu747fs)]

NM_000179.3(MSH6):c.2238dup (p.Leu747fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.2238dup (p.Leu747fs)

HGVS:

NC_000002.12:g.47800221dup
NG_007111.1:g.22075dup
NM_000179.3:c.2238dupMANE SELECT
NM_001281492.2:c.1848dup
NM_001281493.2:c.1332dup
NM_001281494.2:c.1332dup
NP_000170.1:p.Leu747fs
NP_000170.1:p.Leu747fs
NP_001268421.1:p.Leu617fs
NP_001268422.1:p.Leu445fs
NP_001268423.1:p.Leu445fs
LRG_219t1:c.2238dup
LRG_219:g.22075dup
LRG_219p1:p.Leu747fs
NC_000002.11:g.48027355_48027356insT
NC_000002.11:g.48027360dup
NM_000179.2:c.2238dup
NM_000179.2:c.2238dupT

Protein change:

L445fs

Links:

dbSNP: rs1553413599

NCBI 1000 Genomes Browser:

rs1553413599

Molecular consequence:

NM_000179.3:c.2238dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.1848dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.1332dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.1332dup - 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
SCV000624737	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 13, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24362816, 18269114, 30013564, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000624737

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 13, 2021)

germline

clinical testing

PubMed (4)
[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

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

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000624737.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). This variant has been observed in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 30013564).¬†ClinVar contains an entry for this variant (Variation ID: 455182). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu747Serfs*9) in the MSH6 gene. It is expected to result in an absent or disrupted protein product.

#	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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