NM_000179.3(MSH6):c.2062_2063del (p.Val688fs) 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:: RCV000074711.7

Allele description [Variation Report for NM_000179.3(MSH6):c.2062_2063del (p.Val688fs)]

NM_000179.3(MSH6):c.2062_2063del (p.Val688fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.2062_2063del (p.Val688fs)

HGVS:

NC_000002.11:g.48027184_48027185del
NC_000002.12:g.47800043GT[1]
NG_007111.1:g.21897GT[1]
NM_000179.3:c.2062_2063delMANE SELECT
NM_001281492.2:c.1672_1673del
NM_001281493.2:c.1156_1157del
NM_001281494.2:c.1156_1157del
NP_000170.1:p.Val688fs
NP_001268421.1:p.Val558fs
NP_001268422.1:p.Val386fs
NP_001268423.1:p.Val386fs
LRG_219:g.21897GT[1]
NC_000002.11:g.48027181_48027182del
NC_000002.11:g.48027182GT[1]
NC_000002.11:g.48027184_48027185del
NM_000179.2:c.2062_2063delGT
NM_000179.3:c.2062_2063del
p.V688LFS*9

Protein change:

V386fs

Links:

dbSNP: rs63750075

NCBI 1000 Genomes Browser:

rs63750075

Molecular consequence:

NM_000179.3:c.2062_2063del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.1672_1673del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.1156_1157del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.1156_1157del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000107918	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV004843779	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11807791, 15483016, 18301448, 27601186, 28938458, 30128536, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000107918

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV004843779

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (7)
[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	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation.

Plaschke J, Krüger S, Pistorius S, Theissig F, Saeger HD, Schackert HK.

Int J Cancer. 2002 Feb 10;97(5):643-8.

PubMed [citation]

PMID:: 11807791

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

See all PubMed Citations (7)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107918.3

#	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 All of Us Research Program, National Institutes of Health, SCV004843779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

This variant deletes one nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 11807791, 15483016, 18301448, 27601186) and Lynch syndrome-associated cancers (PMID: 28938458). This variant has also been identified in an individual affected with breast cancer (PMID: 30128536). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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