NM_000179.3(MSH6):c.727C>T (p.Arg243Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 14, 2023
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:: RCV000132028.12

Allele description [Variation Report for NM_000179.3(MSH6):c.727C>T (p.Arg243Cys)]

NM_000179.3(MSH6):c.727C>T (p.Arg243Cys)

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.727C>T (p.Arg243Cys)

HGVS:

NC_000002.12:g.47798710C>T
NG_007111.1:g.20564C>T
NM_000179.3:c.727C>TMANE SELECT
NM_001281492.2:c.337C>T
NM_001281493.2:c.-180C>T
NM_001281494.2:c.-180C>T
NP_000170.1:p.Arg243Cys
NP_000170.1:p.Arg243Cys
NP_001268421.1:p.Arg113Cys
LRG_219t1:c.727C>T
LRG_219:g.20564C>T
LRG_219p1:p.Arg243Cys
NC_000002.11:g.48025849C>T
NM_000179.2:c.727C>T
p.R243C

Protein change:

R113C

Links:

dbSNP: rs377216828

NCBI 1000 Genomes Browser:

rs377216828

Molecular consequence:

NM_001281493.2:c.-180C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-180C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.337C>T - 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
SCV000187087	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 30267214 Citation Link,
SCV000908357	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 20, 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

SCV000187087

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 14, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000908357

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 20, 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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000187087.10

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

Description

The p.R243C variant (also known as c.727C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 727. The arginine at codon 243 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a high grade glioma (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-2346). 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, SCV000908357.4

#	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 arginine with cysteine at codon 243 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). 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 2/251088 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

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