NM_000179.3(MSH6):c.1190_1191del (p.Tyr397fs) AND Lynch syndrome 5

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002265594.3

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]

Observations:

Condition(s)

Name:: Lynch syndrome 5 (LYNCH5)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 5; Hereditary non-polyposis colorectal cancer, type 5
Identifiers:: MONDO: MONDO:0013710; MedGen: C1833477; Orphanet: 144; OMIM: 614350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002548624	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Jun 23, 2021)	inherited	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15483016, 18301448, 21081928 Citation Link,
SCV004188307	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Aug 11, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002548624

New York Genome Center - CSER-NYCKidSeq

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Pathogenic
(Jun 23, 2021)

inherited

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004188307

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Aug 11, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.

Plaschke J, Engel C, Krüger S, Holinski-Feder E, Pagenstecher C, Mangold E, Moeslein G, Schulmann K, Gebert J, von Knebel Doeberitz M, Rüschoff J, Loeffler M, Schackert HK.

J Clin Oncol. 2004 Nov 15;22(22):4486-94. Epub 2004 Oct 13.

PubMed [citation]

PMID:: 15483016

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 (3)

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV002548624.1

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

Description

The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is the deletion of two nucleotides resulting in a frameshift of the protein at amino acid 397/1361 (exon 4/10), which is predicted to lead to the termination of the protein approximately 3 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reviewedby an Expert Panel and reported in ClinVar as Pathogenic (VarID:89178) and has been reported in several affected individuals in the literature [PMID:15483016,18301448, 21081928]. The inherited c.1190_1191del (p.Tyr397CysfsTer3) variant identified in the MSH6 gene is reported as Pathogenic.

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

From Myriad Genetics, Inc., SCV004188307.1

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

Description

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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

Last Updated: May 12, 2024

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