NM_000251.3(MSH2):c.2649T>G (p.Ile883Met) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004001259.2

Allele description [Variation Report for NM_000251.3(MSH2):c.2649T>G (p.Ile883Met)]

NM_000251.3(MSH2):c.2649T>G (p.Ile883Met)

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.2649T>G (p.Ile883Met)

HGVS:

NC_000002.12:g.47482793T>G
NG_007110.2:g.84670T>G
NM_000251.3:c.2649T>GMANE SELECT
NM_001258281.1:c.2451T>G
NP_000242.1:p.Ile883Met
NP_000242.1:p.Ile883Met
NP_001245210.1:p.Ile817Met
LRG_218t1:c.2649T>G
LRG_218:g.84670T>G
LRG_218p1:p.Ile883Met
NC_000002.11:g.47709932T>G
NM_000251.1:c.2649T>G
NM_000251.2:c.2649T>G

Protein change:

I817M

Links:

dbSNP: rs768983827

NCBI 1000 Genomes Browser:

rs768983827

Molecular consequence:

NM_000251.3:c.2649T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2451T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

Recent activity

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cytochrome b, partial (mitochondrion) [Hemidactylus mindiae]
cytochrome b, partial (mitochondrion) [Hemidactylus mindiae]
gi|334367007|gb|AEE37258.1|

Protein
recombination activating protein 1, partial [Hemidactylus mindiae]
recombination activating protein 1, partial [Hemidactylus mindiae]
gi|510032245|gb|AGN32705.1|

Protein
Ameerega sp. JLB-2009a isolate 5 16S ribosomal RNA gene, partial sequence; mitoc...
Ameerega sp. JLB-2009a isolate 5 16S ribosomal RNA gene, partial sequence; mitochondrial
gi|226856896|gb|FJ752295.1|

Nucleotide
Ameerega sp. JLB-2009a isolate 4 cytochrome b (cytb) gene, partial cds; mitochon...
Ameerega sp. JLB-2009a isolate 4 cytochrome b (cytb) gene, partial cds; mitochondrial
gi|226856961|gb|FJ752335.1|

Nucleotide
Tetramolopium mitiaroense isolate 7952 external transcribed spacer, partial sequ...
Tetramolopium mitiaroense isolate 7952 external transcribed spacer, partial sequence
gi|2308269676|gb|MZ511160.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004826587	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25110875, 29442399, 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004826587

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (4)
[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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers.

Kang SY, Park CK, Chang DK, Kim JW, Son HJ, Cho YB, Yun SH, Kim HC, Kwon M, Kim KM.

Int J Cancer. 2015 Apr 1;136(7):1568-78. doi: 10.1002/ijc.29133. Epub 2014 Aug 22.

PubMed [citation]

PMID:: 25110875

Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution.

Lee HJ, Choi MC, Jang JH, Jung SG, Park H, Joo WD, Kim TH, Lee C, Lee JH.

J Obstet Gynaecol Res. 2018 May;44(5):944-950. doi: 10.1111/jog.13603. Epub 2018 Feb 14.

PubMed [citation]

PMID:: 29442399

See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004826587.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces isoleucine with methionine at codon 883 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 25110875, 29442399), however, in one of these individuals this variant co-occurred with another potentially pathogenic MSH2 variant (PMID: 29442399). This variant has been identified in 3/282316 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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