NM_000251.3(MSH2):c.680_683del (p.Arg227fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 4, 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:: RCV000491538.7

Allele description [Variation Report for NM_000251.3(MSH2):c.680_683del (p.Arg227fs)]

NM_000251.3(MSH2):c.680_683del (p.Arg227fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.680_683del (p.Arg227fs)

HGVS:

NC_000002.12:g.47412444GAAA[1]
NG_007110.2:g.14321GAAA[1]
NM_000251.3:c.680_683delMANE SELECT
NM_001258281.1:c.482_485del
NP_000242.1:p.Arg227fs
NP_001245210.1:p.Arg161fs
LRG_218:g.14321GAAA[1]
NC_000002.11:g.47639582_47639585del
NC_000002.11:g.47639583GAAA[1]
NM_000251.1:c.680_683delGAAA
NM_000251.2:c.680_683delGAAA
p.R227Kfs*18

Protein change:

R161fs

Links:

dbSNP: rs587782537

NCBI 1000 Genomes Browser:

rs587782537

Molecular consequence:

NM_000251.3:c.680_683del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.482_485del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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

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JGI_CAAK9975.fwd NIH_XGC_tropBrn3 Xenopus tropicalis cDNA clone IMAGE:7660632 5'...
JGI_CAAK9975.fwd NIH_XGC_tropBrn3 Xenopus tropicalis cDNA clone IMAGE:7660632 5', mRNA sequence
gi|58494585|gnl|dbEST|27540636|gb|C 16.1|

Nucleotide
DC129036 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus ...
DC129036 Yamamoto/Hyodo-Miura NIBB/NBRP Xenopus DMZ pCS2p+ cDNA library Xenopus laevis cDNA clone xl320c16 5', mRNA sequence
gi|119075268|gnl|dbEST|43345467|dbj 9036.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186782	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Pathogenic (Apr 11, 2013)	germline	clinical testing	Citation Link,
SCV000580469	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18566915, 24689082 Citation Link,
SCV000903753	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24689082, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186782

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Pathogenic
(Apr 11, 2013)

germline

clinical testing

Citation Link,

SCV000580469

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 4, 2023)

germline

clinical testing

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

Citation Link,

SCV000903753

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 8, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes.

Hansen MF, Neckmann U, Lavik LA, Vold T, Gilde B, Toft RK, Sjursen W.

Mol Genet Genomic Med. 2014 Mar;2(2):186-200. doi: 10.1002/mgg3.62. Epub 2014 Jan 21.

PubMed [citation]

PMID:: 24689082
PMCID:: PMC3960061

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000186782.3

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV000580469.4

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

Description

The c.680_683delGAAA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 680 to 683, causing a translational frameshift with a predicted alternate stop codon (p.R227Kfs*18). This alteration was reported in a Danish Lynch syndrome family; however, clinical details were not provided (Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, SCV000903753.2

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

Description

This variant deletes 4 nucleotides in exon 4 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with colorectal cancer (PMID: 24689082). 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

Last Updated: Jun 9, 2024

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