NM_000179.3(MSH6):c.1450G>A (p.Glu484Lys) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 5, 2023
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:: RCV001340457.5

Allele description [Variation Report for NM_000179.3(MSH6):c.1450G>A (p.Glu484Lys)]

NM_000179.3(MSH6):c.1450G>A (p.Glu484Lys)

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.1450G>A (p.Glu484Lys)

HGVS:

NC_000002.12:g.47799433G>A
NG_007111.1:g.21287G>A
NM_000179.3:c.1450G>AMANE SELECT
NM_001281492.2:c.1060G>A
NM_001281493.2:c.544G>A
NM_001281494.2:c.544G>A
NP_000170.1:p.Glu484Lys
NP_000170.1:p.Glu484Lys
NP_001268421.1:p.Glu354Lys
NP_001268422.1:p.Glu182Lys
NP_001268423.1:p.Glu182Lys
LRG_219t1:c.1450G>A
LRG_219:g.21287G>A
LRG_219p1:p.Glu484Lys
NC_000002.11:g.48026572G>A
NM_000179.2:c.1450G>A

Protein change:

E182K

Links:

dbSNP: rs587782706

NCBI 1000 Genomes Browser:

rs587782706

Molecular consequence:

NM_000179.3:c.1450G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001534266	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32635641, 23621914, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001534266

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 5, 2023)

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

Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals.

Dámaso E, González-Acosta M, Vargas-Parra G, Navarro M, Balmaña J, Ramon Y Cajal T, Tuset N, Thompson BA, Marín F, Fernández A, Gómez C, Velasco À, Solanes A, Iglesias S, Urgel G, López C, Del Valle J, Campos O, Santacana M, Matias-Guiu X, Lázaro C, Valle L, et al.

Cancers (Basel). 2020 Jul 5;12(7). doi: 10.3390/cancers12071799.

PubMed [citation]

PMID:: 32635641
PMCID:: PMC7408773

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20(1):25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001534266.4

#	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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 484 of the MSH6 protein (p.Glu484Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 32635641; Invitae). ClinVar contains an entry for this variant (Variation ID: 216297). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). This variant disrupts the p.Glu484 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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: Nov 24, 2024

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