NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000524185.9

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]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000551262	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17718861, 20028993, 22144684, 24933100, 27443514, 23729658, 24763289, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000551262

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (8)
[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	not provided	not provided	not provided	not provided	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 (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000551262.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant, c.3724_3726del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Arg1242del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781362, gnomAD 0.002%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 17718861, 20028993, 22144684, 24933100, 27443514). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89450). This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23729658, 24763289). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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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