NM_000179.3(MSH6):c.3528_3532del (p.Leu1177fs) AND Hereditary nonpolyposis colon cancer

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 4, 2020
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:: RCV001194361.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3528_3532del (p.Leu1177fs)]

NM_000179.3(MSH6):c.3528_3532del (p.Leu1177fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3528_3532del (p.Leu1177fs)

HGVS:

NC_000002.12:g.47804999_47805003del
NG_007111.1:g.26853_26857del
NG_008397.1:g.105674_105678del
NM_000179.3:c.3528_3532delMANE SELECT
NM_001281492.2:c.3138_3142del
NM_001281493.2:c.2622_2626del
NM_001281494.2:c.2622_2626del
NP_000170.1:p.Leu1177fs
NP_000170.1:p.Leu1177fs
NP_001268421.1:p.Leu1047fs
NP_001268422.1:p.Leu875fs
NP_001268423.1:p.Leu875fs
LRG_219t1:c.3528_3532del
LRG_219:g.26853_26857del
LRG_219p1:p.Leu1177fs
NC_000002.11:g.48032137_48032141del
NC_000002.11:g.48032138_48032142del
NM_000179.2:c.3528_3532del
NM_000179.2:c.3528_3532delACTTG

Protein change:

L1047fs

Links:

dbSNP: rs863225408

NCBI 1000 Genomes Browser:

rs863225408

Molecular consequence:

NM_000179.3:c.3528_3532del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3138_3142del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2622_2626del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2622_2626del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001363847	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 4, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001363847

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Sep 4, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363847.2

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

Description

Variant summary: MSH6 c.3528_3532delACTTG (p.Leu1177CysfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251266 control chromosomes. The variant, c.3528_3532delACTTG, has been reported in the literature in at least one individual in a study of MSH6 mutation carriers (Baglietto_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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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