NM_000179.3(MSH6):c.742C>T (p.Arg248Ter) AND Lynch syndrome

Germline classification:: Pathogenic (3 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:: RCV000075032.8

Allele description [Variation Report for NM_000179.3(MSH6):c.742C>T (p.Arg248Ter)]

NM_000179.3(MSH6):c.742C>T (p.Arg248Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.742C>T (p.Arg248Ter)

Other names:

p.Arg248*

HGVS:

NC_000002.12:g.47798725C>T
NG_007111.1:g.20579C>T
NM_000179.3:c.742C>TMANE SELECT
NM_001281492.2:c.352C>T
NM_001281493.2:c.-165C>T
NM_001281494.2:c.-165C>T
NP_000170.1:p.Arg248Ter
NP_000170.1:p.Arg248Ter
NP_001268421.1:p.Arg118Ter
LRG_219t1:c.742C>T
LRG_219:g.20579C>T
LRG_219p1:p.Arg248Ter
NC_000002.11:g.48025864C>T
NM_000179.2:c.742C>T

Protein change:

R118*

Links:

dbSNP: rs63749980

NCBI 1000 Genomes Browser:

rs63749980

Molecular consequence:

NM_001281493.2:c.-165C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-165C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.742C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.352C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

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

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Sequence 8 from Patent EP2204443
Sequence 8 from Patent EP2204443
gi|300620684|emb|HD063675.1||pat|EP 443|8

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000108253	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV004836941	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10508506, 12547705, 18301448, 33937060, 25741868
SCV004847854	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10508506, 18301448, 12547705, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000108253

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV004836941

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 10, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004847854

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 14, 2019)

germline

clinical testing

PubMed (4)
[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

Unique Combination of Diamond-Blackfan Anemia and Lynch Syndrome in Adult Female: A Case Report.

Tsukanov AS, Pikunov DY, Shubin VP, Barinov AA, Kashnikov VN, Shelygin YA, Kaprin AD, Filonenko EV, Sidorov DV, Maschan AA, Novichkova GA, Yasko LA, Raykina EV, Rumyantsev AG.

Front Oncol. 2021;11:652696. doi: 10.3389/fonc.2021.652696.

PubMed [citation]

PMID:: 33937060
PMCID:: PMC8085342

Familial endometrial cancer in female carriers of MSH6 germline mutations.

Wijnen J, de Leeuw W, Vasen H, van der Klift H, Møller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Möslein G, Tops C, Bröcker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R.

Nat Genet. 1999 Oct;23(2):142-4. No abstract available.

PubMed [citation]

PMID:: 10508506

See all PubMed Citations (5)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108253.3

#	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, SCV004836941.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

This variant changes 1 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, with tumor analyses showing microsatellite instability and/or loss of MSH6 protein by immunohistochemistry analyses (PMID: 10508506, 12547705, 18301448, 33937060). 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847854.1

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

Description

The p.Arg248X variant in MSH6 has been previously reported in 1 individual with Lynch syndrome (Steinke 2008) and 2 individuals with colorectal cancer (Wijnen 1999, Hendricks 2003). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89563). This nonsense variant leads to a premature termination codon at position 248, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.

#	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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