NM_000251.3(MSH2):c.2680dup (p.Met894fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 31, 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:: RCV000657245.5

Allele description [Variation Report for NM_000251.3(MSH2):c.2680dup (p.Met894fs)]

NM_000251.3(MSH2):c.2680dup (p.Met894fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.2680dup (p.Met894fs)

Other names:

p.Met894AsnfsX5

HGVS:

NC_000002.11:g.47709960_47709961insA
NC_000002.12:g.47482824dup
NG_007110.2:g.84701dup
NM_000251.3:c.2680dupMANE SELECT
NM_001258281.1:c.2482dup
NP_000242.1:p.Met894fs
NP_001245210.1:p.Met828fs
LRG_218:g.84701dup
NC_000002.11:g.47709960_47709961insA
NC_000002.11:g.47709963_47709964insA
NC_000002.11:g.47709963dup
NC_000002.12:g.47482824_47482825insA
NM_000251.1:c.2680dupA
NM_000251.2:c.2680dupA
NM_000251.3:c.2680dupAMANE SELECT

Protein change:

M828fs

Links:

dbSNP: rs876658211

NCBI 1000 Genomes Browser:

rs876658211

Molecular consequence:

NM_000251.3:c.2680dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258281.1:c.2482dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000778975	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Aug 22, 2017)	germline	clinical testing	Citation Link,
SCV001449568	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 10, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005090456	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005199189	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 GeneDx, SCV000778975.2

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

Description

This duplication of one nucleotide in MSH2 is denoted c.2680dupA at the cDNA level and p.Met894AsnfsX5 (M894NfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACAA[dupA]TGCC. The duplication causes a frameshift which changes a Methionine to an Asparagine at codon 894, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2680dupA has been reported in individuals with Lynch syndrome, and mismatch repair immunohistochemistry (MMR IHC) data available on a tumor showed loss of MSH2 and MSH6 in at least one carrier (Casey 2005, Lagerstedt-Robinson 2016). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.

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

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449568.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005090456.1

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

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199189.1

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

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

Last Updated: Oct 26, 2024

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