NM_000179.3(MSH6):c.3964_3980dup (p.Asn1327delinsLysAsnLeuArgArgTer) AND Hereditary nonpolyposis colorectal neoplasms

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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 20, 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:: RCV001383244.8

Allele description

NM_000179.3(MSH6):c.3964_3980dup (p.Asn1327delinsLysAsnLeuArgArgTer)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3964_3980dup (p.Asn1327delinsLysAsnLeuArgArgTer)

HGVS:

NC_000002.12:g.47806614_47806630dup
NG_007111.1:g.28468_28484dup
NG_008397.1:g.104047_104063dup
NM_000179.3:c.3964_3980dupMANE SELECT
NM_001281492.2:c.3574_3590dup
NM_001281493.2:c.3058_3074dup
NM_001281494.2:c.3058_3074dup
NP_000170.1:p.Asn1327delinsLysAsnLeuArgArgTer
NP_001268421.1:p.Asn1197delinsLysAsnLeuArgArgTer
NP_001268422.1:p.Asn1025delinsLysAsnLeuArgArgTer
NP_001268423.1:p.Asn1025delinsLysAsnLeuArgArgTer
LRG_219:g.28468_28484dup
NC_000002.11:g.48033751_48033752insAGAATTTGAGAAGATGA
NC_000002.11:g.48033753_48033769dup

Links:

dbSNP: rs2104565388

NCBI 1000 Genomes Browser:

rs2104565388

Molecular consequence:

NM_000179.3:c.3964_3980dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281492.2:c.3574_3590dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281493.2:c.3058_3074dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001281494.2:c.3058_3074dup - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001582332	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 20, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14520694, 15236168, 16237223, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001582332

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 20, 2020)

germline

clinical testing

PubMed (4)
[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

MSH6 germline mutations are rare in colorectal cancer families.

Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA.

Int J Cancer. 2003 Nov 20;107(4):571-9.

PubMed [citation]

PMID:: 14520694

Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.

Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, Sandkuijl L, Møller P, Genuardi M, Van Houwelingen H, Tops C, Van Puijenbroek M, Verkuijlen P, Kenter G, Van Mil A, Meijers-Heijboer H, Tan GB, Breuning MH, Fodde R, Wijnen JT, Bröcker-Vriends AH, Vasen H.

Gastroenterology. 2004 Jul;127(1):17-25.

PubMed [citation]

PMID:: 15236168

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001582332.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the MSH6 protein. Other variant(s) that disrupt this region (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 15236168, 16237223). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MSH6 gene (p.Asn1327Lysfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acids of the MSH6 protein.

#	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: Feb 28, 2024

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