NM_000179.3(MSH6):c.3519_3522dup (p.Thr1175fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 22, 2024
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:: RCV004019096.1

Allele description [Variation Report for NM_000179.3(MSH6):c.3519_3522dup (p.Thr1175fs)]

NM_000179.3(MSH6):c.3519_3522dup (p.Thr1175fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3519_3522dup (p.Thr1175fs)

HGVS:

NC_000002.12:g.47804990_47804993dup
NG_007111.1:g.26844_26847dup
NG_008397.1:g.105684_105687dup
NM_000179.3:c.3519_3522dupMANE SELECT
NM_001281492.2:c.3129_3132dup
NM_001281493.2:c.2613_2616dup
NM_001281494.2:c.2613_2616dup
NP_000170.1:p.Thr1175fs
NP_001268421.1:p.Thr1045fs
NP_001268422.1:p.Thr873fs
NP_001268423.1:p.Thr873fs
LRG_219:g.26844_26847dup
NC_000002.11:g.48032129_48032132dup
NM_000179.2:c.3519_3522dupGTTT
p.Thr1175Valfs*3

Protein change:

T1045fs

Links:

dbSNP: rs267608101

NCBI 1000 Genomes Browser:

rs267608101

Molecular consequence:

NM_000179.3:c.3519_3522dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3129_3132dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2613_2616dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2613_2616dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005032889	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 22, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18625694, 22081473 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005032889

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 22, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting.

Ramsoekh D, Wagner A, van Leerdam ME, Dinjens WN, Steyerberg EW, Halley DJ, Kuipers EJ, Dooijes D.

Gut. 2008 Nov;57(11):1539-44. doi: 10.1136/gut.2008.156695. Epub 2008 Jul 14.

PubMed [citation]

PMID:: 18625694

Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome.

van Lier MG, Leenen CH, Wagner A, Ramsoekh D, Dubbink HJ, van den Ouweland AM, Westenend PJ, de Graaf EJ, Wolters LM, Vrijland WW, Kuipers EJ, van Leerdam ME, Steyerberg EW, Dinjens WN; LIMO Study Group..

J Pathol. 2012 Apr;226(5):764-74. doi: 10.1002/path.3963. Epub 2012 Jan 17.

PubMed [citation]

PMID:: 22081473

Details of each submission

From Ambry Genetics, SCV005032889.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.3519_3522dupGTTT pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a duplication of GTTT at nucleotide position 3519, causing a translational frameshift with a predicted alternate stop codon (p.T1175Vfs*3). This mutation was detected in a proband with colorectal cancer that demonstrated high microsatellite instability and loss of MSH6 staining by immunohistochemistry (IHC) (van Lier MG et al. J Pathol, 2012 Apr;226:764-74), and was also detected in 1/108 Dutch families with a clinical suspicion of Lynch syndrome (Ramsoekh D et al. Gut, 2008 Nov;57:1539-44). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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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