NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 20, 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:: RCV000115494.17

Allele description [Variation Report for NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)]

NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter)

Other names:

p.R389*:CGA>TGA

HGVS:

NC_000002.12:g.47429830C>T
NG_007110.2:g.31707C>T
NM_000251.3:c.1165C>TMANE SELECT
NM_001258281.1:c.967C>T
NP_000242.1:p.Arg389Ter
NP_000242.1:p.Arg389Ter
NP_001245210.1:p.Arg323Ter
LRG_218t1:c.1165C>T
LRG_218:g.31707C>T
LRG_218p1:p.Arg389Ter
NC_000002.11:g.47656969C>T
NM_000251.1:c.1165C>T
NM_000251.2:c.1165C>T
NM_000251.3:c.1165C>T
p.Arg389*
p.Arg389Stop
p.R389*

Protein change:

R323*

Links:

dbSNP: rs587779075

NCBI 1000 Genomes Browser:

rs587779075

Molecular consequence:

NM_000251.3:c.1165C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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
SCV000184319	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 16, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15235030, 16639607, 22883484, 25117503, 25430799, 25569433, 25648859 Citation Link,
SCV000537676	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21642682, 21868491, 22883484, 25117503, 25648859, 28874130, 25741868
SCV002528817	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Oct 29, 2021)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 15235030, 15713769, 15849733, 19698169, 25117503, 25648859, 26681312, 31054147, 31857677, 15855432 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184319

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 16, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000537676

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 20, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002528817

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Oct 29, 2021)

germline

curation

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical, and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer.

Mongiat-Artus P, Miquel C, Fléjou JF, Coulet F, Verine J, Buhard O, Soliman H, Teillac P, Praz F.

Virchows Arch. 2006 Aug;449(2):238-43. Epub 2006 Apr 26.

PubMed [citation]

PMID:: 16639607

Genetic features of Lynch syndrome in the Israeli population.

Goldberg Y, Barnes-Kedar I, Lerer I, Halpern N, Plesser M, Hubert A, Kadouri L, Goldshmidt H, Solar I, Strul H, Rosner G, Baris HN, Peretz T, Levi Z, Kariv R.

Clin Genet. 2015 Jun;87(6):549-53. doi: 10.1111/cge.12530. Epub 2014 Nov 28.

PubMed [citation]

PMID:: 25430799

See all PubMed Citations (18)

Details of each submission

From Ambry Genetics, SCV000184319.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.R389* pathogenic mutation (also known as c.1165C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1165. This changes the amino acid from an arginine to a stop codon within coding exon 7. This alteration has been reported in multiple individuals from several populations meeting Amsterdam criteria, with features of Muir-Torre syndrome, or with Lynch-syndrome related tumors with absent MSH2 IHC expression and/or microsatellite instability (Mangold E et al. J. Med. Genet. 2004 Jul;41:567-72; Roupret M et al. J. Med. Genet. 2004 Jul;41(7):e91; Mongiat-Artus P et al. Virchows Arch. 2006 Aug;449:238-43; Skeldon SC et al. Eur. Urol. 2013 Feb;63:379-85; Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82; Therkildsen C et al. Eur. J. Neurol. 2015 Apr;22:717-24; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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, SCV000537676.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant changes 1 nucleotide in exon 7 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 21642682, 25117503, 25648859, 28874130) and in individuals affected with colorectal cancer, whose tumors showed the absence of MSH2 protein expression and microsatellite instability (PMID: 21868491, 22883484). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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 Sema4, Sema4, SCV002528817.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

#	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 13, 2024

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