NM_000179.3(MSH6):c.1450G>A (p.Glu484Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 21, 2024
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:: RCV001011654.4

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 cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001172001	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 21, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001172001

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 21, 2024)

germline

clinical testing

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

Citation Link

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

Details of each submission

From Ambry Genetics, SCV001172001.5

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

Description

The p.E484K pathogenic mutation (also known as c.1450G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1450. The glutamic acid at codon 484 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an individual with MSI-H colorectal cancer that showed loss of MSH6 protein by immunohistochemistry; this individual also met Amsterdam criteria for Lynch syndrome (Dámaso E et al. Cancers (Basel), 2020 Jul;12:). Based on internal structural analysis, this variant is deleterious, is moderately destabilizing to the local structure, and is more destabilizing than nearby likely pathogenic variants (Ambry internal data). Another variant at the same codon, p.E484Q (c.1450G>C), has been identified in trans with another pathogenic MSH6 mutation in an individual with clinical features of CMMRD (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

#	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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