NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs) AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 15, 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:: RCV001263515.1

Allele description [Variation Report for NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)]

NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)

HGVS:

NC_000002.12:g.47806256_47806259del
NG_007111.1:g.28110_28113del
NG_008397.1:g.104419_104422del
NM_000179.3:c.3699_3702delMANE SELECT
NM_001281492.2:c.3309_3312del
NM_001281493.2:c.2793_2796del
NM_001281494.2:c.2793_2796del
NP_000170.1:p.Lys1233fs
NP_001268421.1:p.Lys1103fs
NP_001268422.1:p.Lys931fs
NP_001268423.1:p.Lys931fs
LRG_219:g.28110_28113del
NC_000002.11:g.48033393_48033396del
NC_000002.11:g.48033395_48033398del
NM_000179.2:c.3699_3702delAGAA
NM_000179.3:c.3699_3702del
p.K1233NFS*6
p.Lys1233Asnfs*6
p.Lys1233AsnfsX6

Protein change:

K1103fs

Links:

dbSNP: rs193922343

NCBI 1000 Genomes Browser:

rs193922343

Molecular consequence:

NM_000179.3:c.3699_3702del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3309_3312del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2793_2796del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2793_2796del - 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
SCV000052938	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21642682, 25430799, 24933100, 25213678 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000052938

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 15, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, et al.

JAMA. 2011 Jun 8;305(22):2304-10. doi: 10.1001/jama.2011.743.

PubMed [citation]

PMID:: 21642682

Genetic features of Lynch syndrome in the Israeli population.

Goldberg Y, Barnes-Kedar I, Lerer I, Halpern N, Plesser M, Hubert A, Kadouri L, Goldshmidt H, Solar I, Strul H, Rosner G, Baris HN, Peretz T, Levi Z, Kariv R.

Clin Genet. 2015 Jun;87(6):549-53. doi: 10.1111/cge.12530. Epub 2014 Nov 28.

PubMed [citation]

PMID:: 25430799

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052938.3

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

Description

Variant summary: MSH6 c.3699_3702delAGAA (p.Lys1233AsnfsX6) 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 allele was found at a frequency of 4e-06 in 251238 control chromosomes. c.3699_3702delAGAA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Goldberg_2014, Bonadona_2011, Batte_2014, Raymond_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 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: Nov 24, 2024

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