NM_000179.3(MSH6):c.3543C>A (p.Asp1181Glu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 27, 2022
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:: RCV000702066.8

Allele description [Variation Report for NM_000179.3(MSH6):c.3543C>A (p.Asp1181Glu)]

NM_000179.3(MSH6):c.3543C>A (p.Asp1181Glu)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3543C>A (p.Asp1181Glu)

HGVS:

NC_000002.12:g.47805014C>A
NG_007111.1:g.26868C>A
NG_008397.1:g.105662G>T
NM_000179.3:c.3543C>AMANE SELECT
NM_001281492.2:c.3153C>A
NM_001281493.2:c.2637C>A
NM_001281494.2:c.2637C>A
NP_000170.1:p.Asp1181Glu
NP_000170.1:p.Asp1181Glu
NP_001268421.1:p.Asp1051Glu
NP_001268422.1:p.Asp879Glu
NP_001268423.1:p.Asp879Glu
LRG_219t1:c.3543C>A
LRG_219:g.26868C>A
LRG_219p1:p.Asp1181Glu
NC_000002.11:g.48032153C>A
NM_000179.2:c.3543C>A

Protein change:

D1051E

Links:

dbSNP: rs267608100

NCBI 1000 Genomes Browser:

rs267608100

Molecular consequence:

NM_000179.3:c.3543C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3153C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2637C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2637C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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dbVar for Gene (Select 51274) (261)
dbVar
KLF3 KLF transcription factor 3 [Homo sapiens]
KLF3 KLF transcription factor 3 [Homo sapiens]
Gene ID:51274

Gene
Gene Links for OMIM (Select 609392) (1)
Gene
Conserved Domain Links for Gene (Select 51274) (4)
Conserved Domains

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000830900	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18566915, 22495361, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000830900

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 27, 2022)

germline

clinical testing

PubMed (3)
[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

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry.

Okkels H, Lindorff-Larsen K, Thorlasius-Ussing O, Vyberg M, Lindebjerg J, Sunde L, Bernstein I, Klarskov L, Holck S, Krarup HB.

Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7. doi: 10.1097/PAI.0b013e318249739b.

PubMed [citation]

PMID:: 22495361

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830900.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1181 of the MSH6 protein (p.Asp1181Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 18566915, 22495361). This missense change has been observed to co-occur in individuals with a different variant in MSH6 that has been determined to be pathogenic (PMID: 18566915, 22495361), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 578919). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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