NM_001281492.1(MSH6):c.1760_1763del (p.Val587fs) AND Lynch syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 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:: RCV000074720.3

Allele description

NM_001281492.1(MSH6):c.1760_1763del (p.Val587fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_001281492.1(MSH6):c.1760_1763del (p.Val587fs)

HGVS:

NC_000002.12:g.47800133_47800136del
NG_007111.1:g.21987_21990del
NM_001281492.1:c.1760_1763del
NM_001281493.1:c.1244_1247del
NM_001281494.1:c.1244_1247del
NP_001268421.1:p.Val587fs
NP_001268422.1:p.Val415fs
NP_001268423.1:p.Val415fs
LRG_219t1:c.2150_2153del
LRG_219:g.21987_21990del
LRG_219p1:p.Val717fs
NC_000002.11:g.48027272_48027275del
NM_000179.2:c.2150_2153delTCAG
p.V717Afs*18

Protein change:

V415fs

Links:

dbSNP: rs267608058

NCBI 1000 Genomes Browser:

rs267608058

Molecular consequence:

NM_001281492.1:c.1760_1763del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.1:c.1244_1247del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.1:c.1244_1247del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Lynch syndrome
Synonyms:: Familial nonpolyposis colon cancer
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000107928	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000266092	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000592599	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2013)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10537275, 18566915, 23047549, 22006311, 25741868
SCV000695800	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 2, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10537275, 18566915, 20487569, 23047549, 22006311 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (7)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000107928.2

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000266092.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	not provided	1	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	no	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592599.1

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

#	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 Integrated Genetics/Laboratory Corporation of America, SCV000695800.1

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

Description

Variant summary: The MSH6 c.2150_2153delTCAG (p.Val717Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/121546 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, ExAC indicates that the location is a low-quality site, therefore, this observation needs to be cautiously considered. Multiple publications cite the variant in affected individuals including one family (Talseth-Palmer_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 3, 2021

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