NM_000179.3(MSH6):c.698C>G (p.Pro233Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000131704.11

Allele description [Variation Report for NM_000179.3(MSH6):c.698C>G (p.Pro233Arg)]

NM_000179.3(MSH6):c.698C>G (p.Pro233Arg)

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.698C>G (p.Pro233Arg)

Other names:

p.P233R:CCT>CGT

HGVS:

NC_000002.12:g.47798681C>G
NG_007111.1:g.20535C>G
NM_000179.3:c.698C>GMANE SELECT
NM_001281492.2:c.308C>G
NM_001281493.2:c.-209C>G
NM_001281494.2:c.-209C>G
NP_000170.1:p.Pro233Arg
NP_000170.1:p.Pro233Arg
NP_001268421.1:p.Pro103Arg
LRG_219t1:c.698C>G
LRG_219:g.20535C>G
LRG_219p1:p.Pro233Arg
NC_000002.11:g.48025820C>G
NM_000179.2:c.698C>G
p.P233R

Protein change:

P103R

Links:

dbSNP: rs142949377

NCBI 1000 Genomes Browser:

rs142949377

Molecular consequence:

NM_001281493.2:c.-209C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-209C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.698C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.308C>G - 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

Recent activity

Clear Turn Off Turn On

CJ317104 RIKEN full-length enriched mouse cDNA library, Rathke's pouches 14.5 da...
CJ317104 RIKEN full-length enriched mouse cDNA library, Rathke's pouches 14.5 days embryo Mus musculus cDNA clone M230016C14 3', mRNA sequence
gi|76541299|gnl|dbEST|32163035|dbj| 104.1|

Nucleotide
chromodomain-helicase-DNA-binding protein 8 isoform 1 [Homo sapiens]
chromodomain-helicase-DNA-binding protein 8 isoform 1 [Homo sapiens]
gi|282165704|ref|NP_001164100.1|

Protein
Rattus norvegicus glutamate-rich WD repeat containing 1, mRNA (cDNA clone MGC:95...
Rattus norvegicus glutamate-rich WD repeat containing 1, mRNA (cDNA clone MGC:95187 IMAGE:7131596), complete cds
gi|53734293|gb|BC083883.1|

Nucleotide
Taxonomy Links for Protein (Select 219518500) (1)
Taxonomy
Saccharomyces cerevisiae
Saccharomyces cerevisiae
snf/swi mutants of S. cerevisiae.

BioProject

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186742	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000685516	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 27, 2023)	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

SCV000186742

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 25, 2024)

germline

clinical testing

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

Citation Link,

SCV000685516

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 27, 2023)

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

Rare loss of function variants in candidate genes and risk of colorectal cancer.

Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U, Jarvik GP; NHLBI GO Exome Sequencing Project..

Hum Genet. 2018 Oct;137(10):795-806. doi: 10.1007/s00439-018-1938-4. Epub 2018 Sep 28.

PubMed [citation]

PMID:: 30267214
PMCID:: PMC6283057

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 Ambry Genetics, SCV000186742.8

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

Description

The p.P233R variant (also known as c.698C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 698. The proline at codon 233 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000685516.4

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

Description

This missense variant replaces proline with arginine at codon 233 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/250858 chromosomes 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine