NM_000179.3(MSH6):c.1480G>T (p.Ala494Ser) AND Lynch syndrome

delete

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 1, 2016
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:: RCV000459292.1

Allele description

NM_000179.3(MSH6):c.1480G>T (p.Ala494Ser)

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.1480G>T (p.Ala494Ser)

HGVS:

NC_000002.12:g.47799463G>T
NG_007111.1:g.21317G>T
NM_000179.3:c.1480G>TMANE SELECT
NM_001281492.2:c.1090G>T
NM_001281493.2:c.574G>T
NM_001281494.2:c.574G>T
NP_000170.1:p.Ala494Ser
NP_000170.1:p.Ala494Ser
NP_001268421.1:p.Ala364Ser
NP_001268422.1:p.Ala192Ser
NP_001268423.1:p.Ala192Ser
LRG_219t1:c.1480G>T
LRG_219:g.21317G>T
LRG_219p1:p.Ala494Ser
NC_000002.11:g.48026602G>T
NM_000179.2:c.1480G>T

Protein change:

A192S

Links:

dbSNP: rs758699749

NCBI 1000 Genomes Browser:

rs758699749

Molecular consequence:

NM_000179.3:c.1480G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1090G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.574G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.574G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000551214	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 1, 2016)	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

SCV000551214

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 1, 2016)

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000551214.2

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

Description

This sequence change replaces alanine with serine at codon 494 of the MSH6 protein (p.Ala494Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs758699749, ExAC 0.006%) but has not been reported in the literature in individuals with a MSH6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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: Apr 23, 2022

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