NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del) AND Lynch syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 21, 2019
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:: RCV000074918.6

Allele description [Variation Report for NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)]

NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)

HGVS:

NC_000002.12:g.47806281_47806283del
NG_007111.1:g.28135_28137del
NG_008397.1:g.104395_104397del
NM_000179.3:c.3724_3726delMANE SELECT
NM_001281492.2:c.3334_3336del
NM_001281493.2:c.2818_2820del
NM_001281494.2:c.2818_2820del
NP_000170.1:p.Arg1242del
NP_001268421.1:p.Arg1112del
NP_001268422.1:p.Arg940del
NP_001268423.1:p.Arg940del
LRG_219:g.28135_28137del
NC_000002.11:g.48033418_48033420del
NC_000002.11:g.48033420_48033422del
NM_000179.2:c.3724_3726delCGT
p.R1242del

Protein change:

R1112del

Links:

dbSNP: rs63749942

NCBI 1000 Genomes Browser:

rs63749942

Molecular consequence:

NM_000179.3:c.3724_3726del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.3334_3336del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.2818_2820del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.2818_2820del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000108130	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Likely pathogenic (Jun 21, 2019)	germline	curation	Citation Link,
SCV004835119	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17718861, 20028993, 24362816, 24933100, 27443514, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000108130

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Likely pathogenic
(Jun 21, 2019)

germline

curation

Citation Link,

SCV004835119

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 8, 2023)

germline

clinical testing

PubMed (6)
[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	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC.

Roncari B, Pedroni M, Maffei S, Di Gregorio C, Ponti G, Scarselli A, Losi L, Benatti P, Roncucci L, De Gaetani C, Camellini L, Lucci-Cordisco E, Tricarico R, Genuardi M, Ponz de Leon M.

Clin Genet. 2007 Sep;72(3):230-7.

PubMed [citation]

PMID:: 17718861

Risks of Lynch syndrome cancers for MSH6 mutation carriers.

Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study Group., Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, Macrae F, Antill Y, Winship IM, Giles GG, et al.

J Natl Cancer Inst. 2010 Feb 3;102(3):193-201. doi: 10.1093/jnci/djp473. Epub 2009 Dec 22.

PubMed [citation]

PMID:: 20028993
PMCID:: PMC2815724

See all PubMed Citations (6)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000108130.3

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

Description

Multifactorial likelihood analysis posterior probability 0.95-0.99

#	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 All of Us Research Program, National Institutes of Health, SCV004835119.1

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

Description

This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. 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		2	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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