NM_000179.3(MSH6):c.3476dup (p.Tyr1159Ter) AND Lynch syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 14, 2017
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:: RCV000607246.7

Allele description [Variation Report for NM_000179.3(MSH6):c.3476dup (p.Tyr1159Ter)]

NM_000179.3(MSH6):c.3476dup (p.Tyr1159Ter)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3476dup (p.Tyr1159Ter)

Other names:

p.Tyr1159X; p.Tyr1159*

HGVS:

NC_000002.11:g.48032085_48032086insA
NC_000002.12:g.47804947dup
NG_007111.1:g.26801dup
NG_008397.1:g.105729dup
NM_000179.3:c.3476dupMANE SELECT
NM_001281492.2:c.3086dup
NM_001281493.2:c.2570dup
NM_001281494.2:c.2570dup
NP_000170.1:p.Tyr1159Ter
NP_000170.1:p.Tyr1159Ter
NP_001268421.1:p.Tyr1029Ter
NP_001268422.1:p.Tyr857Ter
NP_001268423.1:p.Tyr857Ter
LRG_219t1:c.3476dup
LRG_219:g.26801dup
LRG_219p1:p.Tyr1159Ter
NC_000002.11:g.48032085_48032086insA
NC_000002.11:g.48032086_48032087insA
NC_000002.11:g.48032086dup
NM_000179.2:c.3476dup
NM_000179.2:c.3476dup
NM_000179.2:c.3476dupA
p.Y1159*

Protein change:

Y1029*

Links:

dbSNP: rs587782111

NCBI 1000 Genomes Browser:

rs587782111

Molecular consequence:

NM_000179.3:c.3476dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.3086dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281493.2:c.2570dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281494.2:c.2570dup - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000731759	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 14, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21642682, 21868491, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000731759

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jul 14, 2017)

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	not provided	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, et al.

JAMA. 2011 Jun 8;305(22):2304-10. doi: 10.1001/jama.2011.743.

PubMed [citation]

PMID:: 21642682

Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer.

Pérez-Carbonell L, Ruiz-Ponte C, Guarinos C, Alenda C, Payá A, Brea A, Egoavil CM, Castillejo A, Barberá VM, Bessa X, Xicola RM, Rodríguez-Soler M, Sánchez-Fortún C, Acame N, Castellví-Bel S, Piñol V, Balaguer F, Bujanda L, De-Castro ML, Llor X, Andreu M, Carracedo A, et al.

Gut. 2012 Jun;61(6):865-72. doi: 10.1136/gutjnl-2011-300041. Epub 2011 Aug 25.

PubMed [citation]

PMID:: 21868491

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731759.1

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

Description

The p.Tyr1159X (c.3476_3477insA) variant in MSH6 has not been previously reporte d in the literature, but has been reported in ClinVar by other clinical laborato ries (Variation ID# 141918). This variant was absent from large population studi es. This nonsense variant leads to a premature termination codon at position 115 9, which is predicted to lead to a truncated or absent protein. Heterozygous los s of function of the MSH6 gene is an established disease mechanism in Lynch synd rome. Another nonsense variant at an adjacent nucleotide position (c.3477C>A) th at results in the same amino acid change has been reported in two individuals wi th Lynch syndrome (Perez-Carbonell 2010 and Bonadona 2011). Microsatellite inst ability was documented in the individual reported (Perez-Carbonell 2010). In sum mary, this variant meets criteria to be classified as pathogenic for Lynch syndr ome in an autosomal dominant manner based upon the predicted impact to the prote in and absence from controls.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	3	not provided

Last Updated: Oct 26, 2024

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