NM_000179.3(MSH6):c.742C>T (p.Arg248Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 21, 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:: RCV000486750.10

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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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
SCV000566643	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 21, 2023)	germline	clinical testing	Citation Link,
SCV001134456	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 25, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10508506, 18301448, 12547705, 26467025
SCV002760657	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226587	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10508506, 12547705, 18301448, 31307542, 33937060, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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 (7)

Details of each submission

From GeneDx, SCV000566643.6

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal and/or family history of MSH6-related cancers (PMID: 10508506, 18301448, 33937060); This variant is associated with the following publications: (PMID: 25525159, 33087929, 33937060, 30787465, 10508506, 15236168, 12547705, 20028993, 18301448, 29625052, 28502729, 33309985)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134456.3

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

Description

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002760657.3

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

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226587.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

PP4, PP5, PM2, PVS1

#	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		2	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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