NM_000179.3(MSH6):c.2116T>A (p.Phe706Ile) AND Hereditary nonpolyposis colorectal neoplasms

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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 17, 2021
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:: RCV002036634.5

Allele description

NM_000179.3(MSH6):c.2116T>A (p.Phe706Ile)

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.2116T>A (p.Phe706Ile)

HGVS:

NC_000002.12:g.47800099T>A
NG_007111.1:g.21953T>A
NM_000179.3:c.2116T>AMANE SELECT
NM_001281492.2:c.1726T>A
NM_001281493.2:c.1210T>A
NM_001281494.2:c.1210T>A
NP_000170.1:p.Phe706Ile
NP_001268421.1:p.Phe576Ile
NP_001268422.1:p.Phe404Ile
NP_001268423.1:p.Phe404Ile
LRG_219:g.21953T>A
NC_000002.11:g.48027238T>A

Protein change:

F404I

Links:

dbSNP: rs2104389521

NCBI 1000 Genomes Browser:

rs2104389521

Molecular consequence:

NM_000179.3:c.2116T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1726T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1210T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1210T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Report on Carcinogens
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gi|537099789|gb|KF442647.1|

Nucleotide
PREDICTED: Homo sapiens SMG6 nonsense mediated mRNA decay factor (SMG6), transcr...
PREDICTED: Homo sapiens SMG6 nonsense mediated mRNA decay factor (SMG6), transcript variant X7, mRNA
gi|2462554232|ref|XM_054315613.1|

Nucleotide
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Chain BV, Ribosomal Protein L23
Chain BV, Ribosomal Protein L23
gi|1995665845|pdb|4V61|BV

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002317679	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 17, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28531214, 17453009, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002317679

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 17, 2021)

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

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

Houlleberghs H, Goverde A, Lusseveld J, Dekker M, Bruno MJ, Menko FH, Mensenkamp AR, Spaander MCW, Wagner A, Hofstra RMW, Te Riele H.

PLoS Genet. 2017 May;13(5):e1006765. doi: 10.1371/journal.pgen.1006765.

PubMed [citation]

PMID:: 28531214
PMCID:: PMC5460888

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer.

Overbeek LI, Kets CM, Hebeda KM, Bodmer D, van der Looij E, Willems R, Goossens M, Arts N, Brunner HG, van Krieken JH, Hoogerbrugge N, Ligtenberg MJ.

Br J Cancer. 2007 May 21;96(10):1605-12. Epub 2007 Apr 24.

PubMed [citation]

PMID:: 17453009
PMCID:: PMC2359954

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002317679.3

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

Description

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. This variant disrupts the p.Phe706 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28531214, 17453009). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces phenylalanine with isoleucine at codon 706 of the MSH6 protein (p.Phe706Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. 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. 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).

#	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: Mar 5, 2024

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