NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 28, 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:: RCV003998593.2

Allele description [Variation Report for NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn)]

NM_000251.3(MSH2):c.1943T>A (p.Ile648Asn)

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.1943T>A (p.Ile648Asn)

HGVS:

NC_000002.12:g.47475208T>A
NG_007110.2:g.77085T>A
NM_000251.3:c.1943T>AMANE SELECT
NM_001258281.1:c.1745T>A
NP_000242.1:p.Ile648Asn
NP_000242.1:p.Ile648Asn
NP_001245210.1:p.Ile582Asn
LRG_218t1:c.1943T>A
LRG_218:g.77085T>A
LRG_218p1:p.Ile648Asn
NC_000002.11:g.47702347T>A
NM_000251.1:c.1943T>A
NM_000251.2:c.1943T>A

Protein change:

I582N

Links:

dbSNP: rs763100088

NCBI 1000 Genomes Browser:

rs763100088

Molecular consequence:

NM_000251.3:c.1943T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1745T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004825050	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Mar 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18990764, 27601186, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004825050

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Mar 28, 2023)

germline

clinical testing

PubMed (3)
[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	108544	not provided	clinical testing

Citations

PubMed

Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening.

Poynter JN, Siegmund KD, Weisenberger DJ, Long TI, Thibodeau SN, Lindor N, Young J, Jenkins MA, Hopper JL, Baron JA, Buchanan D, Casey G, Levine AJ, Le Marchand L, Gallinger S, Bapat B, Potter JD, Newcomb PA, Haile RW, Laird PW; Colon Cancer Family Registry Investigators..

Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):3208-15. doi: 10.1158/1055-9965.EPI-08-0512.

PubMed [citation]

PMID:: 18990764
PMCID:: PMC2628332

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004825050.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces isoleucine with asparagine at codon 648 of the MSH2 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 been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 18990764, 27601186). This variant has been identified in 5/251438 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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