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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 26, 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:: RCV003996994.2

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]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004843610	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32635641, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004843610

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 26, 2023)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	108544	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004843610.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glutamic acid with lysine at codon 484 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer that exhibited microsatellite instability and loss of MSH6 protein by immunohistochemistry analysis (PMID: 32635641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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