NM_000179.3(MSH6):c.670G>C (p.Glu224Gln) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 23, 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:: RCV002726513.3

Allele description [Variation Report for NM_000179.3(MSH6):c.670G>C (p.Glu224Gln)]

NM_000179.3(MSH6):c.670G>C (p.Glu224Gln)

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.670G>C (p.Glu224Gln)

HGVS:

NC_000002.12:g.47798653G>C
NG_007111.1:g.20507G>C
NM_000179.3:c.670G>CMANE SELECT
NM_001281492.2:c.280G>C
NM_001281493.2:c.-237G>C
NM_001281494.2:c.-237G>C
NM_001406795.1:c.766G>C
NM_001406796.1:c.670G>C
NM_001406797.1:c.373G>C
NM_001406798.1:c.670G>C
NM_001406799.1:c.145G>C
NM_001406800.1:c.670G>C
NM_001406801.1:c.373G>C
NM_001406802.1:c.766G>C
NM_001406803.1:c.670G>C
NM_001406804.1:c.592G>C
NM_001406805.1:c.373G>C
NM_001406806.1:c.145G>C
NM_001406807.1:c.145G>C
NM_001406808.1:c.670G>C
NM_001406809.1:c.670G>C
NM_001406811.1:c.-237G>C
NM_001406812.1:c.-237G>C
NM_001406813.1:c.676G>C
NM_001406814.1:c.-237G>C
NM_001406815.1:c.-237G>C
NM_001406816.1:c.-237G>C
NM_001406817.1:c.670G>C
NM_001406818.1:c.373G>C
NM_001406819.1:c.373G>C
NM_001406820.1:c.373G>C
NM_001406821.1:c.373G>C
NM_001406822.1:c.373G>C
NM_001406823.1:c.-237G>C
NM_001406824.1:c.373G>C
NM_001406825.1:c.373G>C
NM_001406826.1:c.502G>C
NM_001406827.1:c.373G>C
NM_001406828.1:c.373G>C
NM_001406829.1:c.-237G>C
NM_001406830.1:c.373G>C
NP_000170.1:p.Glu224Gln
NP_000170.1:p.Glu224Gln
NP_001268421.1:p.Glu94Gln
NP_001393724.1:p.Glu256Gln
NP_001393725.1:p.Glu224Gln
NP_001393726.1:p.Glu125Gln
NP_001393727.1:p.Glu224Gln
NP_001393728.1:p.Glu49Gln
NP_001393729.1:p.Glu224Gln
NP_001393730.1:p.Glu125Gln
NP_001393731.1:p.Glu256Gln
NP_001393732.1:p.Glu224Gln
NP_001393733.1:p.Glu198Gln
NP_001393734.1:p.Glu125Gln
NP_001393735.1:p.Glu49Gln
NP_001393736.1:p.Glu49Gln
NP_001393737.1:p.Glu224Gln
NP_001393738.1:p.Glu224Gln
NP_001393742.1:p.Glu226Gln
NP_001393746.1:p.Glu224Gln
NP_001393747.1:p.Glu125Gln
NP_001393748.1:p.Glu125Gln
NP_001393749.1:p.Glu125Gln
NP_001393750.1:p.Glu125Gln
NP_001393751.1:p.Glu125Gln
NP_001393753.1:p.Glu125Gln
NP_001393754.1:p.Glu125Gln
NP_001393755.1:p.Glu168Gln
NP_001393756.1:p.Glu125Gln
NP_001393757.1:p.Glu125Gln
NP_001393759.1:p.Glu125Gln
LRG_219t1:c.670G>C
LRG_219:g.20507G>C
LRG_219p1:p.Glu224Gln
NC_000002.11:g.48025792G>C
NM_000179.2:c.670G>C
NR_176257.1:n.759G>C
NR_176258.1:n.759G>C
NR_176259.1:n.759G>C
NR_176261.1:n.759G>C

Protein change:

E125Q

Molecular consequence:

NM_001281493.2:c.-237G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-237G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.280G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.766G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.766G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.676G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406817.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.373G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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mitochondrial carnitine/acylcarnitine carrier protein [Xenopus tropicalis]
mitochondrial carnitine/acylcarnitine carrier protein [Xenopus tropicalis]
gi|45360847|ref|NP_989099.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002999996	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002999996

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 23, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002999996.2

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

Description

This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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. 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 not expected to disrupt MSH6 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 224 of the MSH6 protein (p.Glu224Gln).

#	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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