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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:
1

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004825050All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Mar 28, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024