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NM_000251.3(MSH2):c.1787A>T (p.Asn596Ile) AND Lynch syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 7, 2022
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:
RCV004009115.2

Allele description [Variation Report for NM_000251.3(MSH2):c.1787A>T (p.Asn596Ile)]

NM_000251.3(MSH2):c.1787A>T (p.Asn596Ile)

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.1787A>T (p.Asn596Ile)
HGVS:
  • NC_000002.12:g.47475052A>T
  • NG_007110.2:g.76929A>T
  • NM_000251.3:c.1787A>TMANE SELECT
  • NM_001258281.1:c.1589A>T
  • NP_000242.1:p.Asn596Ile
  • NP_001245210.1:p.Asn530Ile
  • LRG_218t1:c.1787A>T
  • LRG_218:g.76929A>T
  • NC_000002.11:g.47702191A>T
  • NM_000251.2:c.1787A>T
Protein change:
N530I
Links:
dbSNP: rs41295288
NCBI 1000 Genomes Browser:
rs41295288
Molecular consequence:
  • NM_000251.3:c.1787A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.1589A>T - 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
SCV004827344All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 7, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]
PMID:
33357406
PMCID:
PMC7820803

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 All of Us Research Program, National Institutes of Health, SCV004827344.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces asparagine with isoleucine at codon 596 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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