NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs) AND Lynch syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000074640.6

Allele description [Variation Report for NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)]

NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs)

HGVS:

NC_000002.12:g.47799173_47799174del
NG_007111.1:g.21027_21028del
NM_000179.3:c.1190_1191delMANE SELECT
NM_001281492.2:c.800_801del
NM_001281493.2:c.284_285del
NM_001281494.2:c.284_285del
NP_000170.1:p.Tyr397fs
NP_001268421.1:p.Tyr267fs
NP_001268422.1:p.Tyr95fs
NP_001268423.1:p.Tyr95fs
LRG_219:g.21027_21028del
NC_000002.11:g.48026311_48026312del
NC_000002.11:g.48026312_48026313del
NM_000179.2:c.1190_1191delAT
p.Tyr397Cysfs*3
p.Y397CfsX3

Protein change:

Y267fs

Links:

dbSNP: rs63750439

NCBI 1000 Genomes Browser:

rs63750439

Molecular consequence:

NM_000179.3:c.1190_1191del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.800_801del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.284_285del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.284_285del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000107842	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000919727	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 15, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14974087, 18301448, 26681312, 21081928 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000107842

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000919727

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 15, 2017)

germline

clinical testing

PubMed (4)
[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, research

Citations

PubMed

Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue.

Plaschke J, Krüger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Möslein G, Rüschoff J, Engel C, Evans G, Schackert HK; German HNPCC Consortium..

Hum Mutat. 2004 Mar;23(3):285.

PubMed [citation]

PMID:: 14974087

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.

Steinke V, Rahner N, Morak M, Keller G, Schackert HK, Görgens H, Schmiegel W, Royer-Pokora B, Dietmaier W, Kloor M, Engel C, Propping P, Aretz S; German HNPCC Consortium..

Eur J Hum Genet. 2008 May;16(5):587-92. doi: 10.1038/ejhg.2008.26. Epub 2008 Feb 27.

PubMed [citation]

PMID:: 18301448

See all PubMed Citations (4)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107842.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

Description

Coding sequence variation resulting in a stop codon

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919727.1

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

Description

Variant summary: The MSH6 c.1190_1191delAT (p.Tyr397CysfsX3) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1444C>T (p.Arg482X), c.1572C>A (p.Tyr524X), c.1634_1637delAAGA (p.Lys545fsX25)). The variant has been observed in patients with HNPCC-associated cancers (i.e. CRC and cancer of the endometrium), in one of them a CRC tumor sample showing loss of MSH6 and microsatellite instability (Plaschke 2004, Susswein 2015). This variant was found in 2/245974 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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: May 12, 2024

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