NM_000179.3(MSH6):c.761C>G (p.Ser254Cys) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 11, 2020
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:: RCV001039832.8

Allele description [Variation Report for NM_000179.3(MSH6):c.761C>G (p.Ser254Cys)]

NM_000179.3(MSH6):c.761C>G (p.Ser254Cys)

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.761C>G (p.Ser254Cys)

HGVS:

NC_000002.12:g.47798744C>G
NG_007111.1:g.20598C>G
NM_000179.3:c.761C>GMANE SELECT
NM_001281492.2:c.371C>G
NM_001281493.2:c.-146C>G
NM_001281494.2:c.-146C>G
NP_000170.1:p.Ser254Cys
NP_001268421.1:p.Ser124Cys
LRG_219t1:c.761C>G
LRG_219:g.20598C>G
NC_000002.11:g.48025883C>G
NM_000179.2:c.761C>G

Protein change:

S124C

Links:

dbSNP: rs876659191

NCBI 1000 Genomes Browser:

rs876659191

Molecular consequence:

NM_001281493.2:c.-146C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-146C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.761C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.371C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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huntingtin-interacting protein 1 isoform 1 [Mus musculus]
huntingtin-interacting protein 1 isoform 1 [Mus musculus]
gi|225007582|ref|NP_666113.2|

Protein
Homo sapiens adenosine deaminase, mRNA (cDNA clone MGC:3971 IMAGE:3629376), comp...
Homo sapiens adenosine deaminase, mRNA (cDNA clone MGC:3971 IMAGE:3629376), complete cds
gi|33873727|gb|BC007678.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001203381	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 11, 2020)	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

SCV001203381

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 11, 2020)

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, SCV001203381.5

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

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 254 of the MSH6 protein (p.Ser254Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine.

#	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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