NM_000179.3(MSH6):c.3761_3764dup (p.Asp1255fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 7, 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:: RCV001384168.5

Allele description [Variation Report for NM_000179.3(MSH6):c.3761_3764dup (p.Asp1255fs)]

NM_000179.3(MSH6):c.3761_3764dup (p.Asp1255fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3761_3764dup (p.Asp1255fs)

HGVS:

NC_000002.12:g.47806318_47806321dup
NG_007111.1:g.28172_28175dup
NG_008397.1:g.104355_104358dup
NM_000179.3:c.3761_3764dupMANE SELECT
NM_001281492.2:c.3371_3374dup
NM_001281493.2:c.2855_2858dup
NM_001281494.2:c.2855_2858dup
NP_000170.1:p.Asp1255fs
NP_001268421.1:p.Asp1125fs
NP_001268422.1:p.Asp953fs
NP_001268423.1:p.Asp953fs
LRG_219t1:c.3761_3764dup
LRG_219:g.28172_28175dup
NC_000002.11:g.48033456_48033457insAAGA
NC_000002.11:g.48033457_48033460dup
NM_000179.2:c.3761_3764dupAAGA

Protein change:

D1125fs

Links:

dbSNP: rs1572745084

NCBI 1000 Genomes Browser:

rs1572745084

Molecular consequence:

NM_000179.3:c.3761_3764dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3371_3374dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2855_2858dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2855_2858dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

Recent activity

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Megalocottus platycephalus isolate MPL3 mitochondrion, complete genome
Megalocottus platycephalus isolate MPL3 mitochondrion, complete genome
gi|1840514272|gb|MK936041.1|

Nucleotide
zinc finger protein 85 isoform b [Homo sapiens]
zinc finger protein 85 isoform b [Homo sapiens]
gi|371873653|ref|NP_001243101.1|

Protein
festoon (0)
Conserved Domains
NISC_mn20f01.x1 NICHD_XGC_Ov1 Xenopus laevis cDNA clone IMAGE:5073937 3', mRNA s...
NISC_mn20f01.x1 NICHD_XGC_Ov1 Xenopus laevis cDNA clone IMAGE:5073937 3', mRNA sequence
gi|21074545|gnl|dbEST|12431683|gb|B 58.1|

Nucleotide
DC110460 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus ...
DC110460 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus laevis cDNA clone xl255j23 5', mRNA sequence
gi|119086412|gnl|dbEST|43356611|dbj 0460.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001583553	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 7, 2023)	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

SCV001583553

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 7, 2023)

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, SCV001583553.4

#	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. ClinVar contains an entry for this variant (Variation ID: 824173). 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.Asp1255Glufs*21) 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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