NM_000251.3(MSH2):c.547C>A (p.Gln183Lys) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 2, 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:: RCV004002418.2

Allele description [Variation Report for NM_000251.3(MSH2):c.547C>A (p.Gln183Lys)]

NM_000251.3(MSH2):c.547C>A (p.Gln183Lys)

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.547C>A (p.Gln183Lys)

HGVS:

NC_000002.12:g.47410274C>A
NG_007110.2:g.12151C>A
NM_000251.3:c.547C>AMANE SELECT
NM_001258281.1:c.349C>A
NP_000242.1:p.Gln183Lys
NP_000242.1:p.Gln183Lys
NP_001245210.1:p.Gln117Lys
LRG_218t1:c.547C>A
LRG_218:g.12151C>A
LRG_218p1:p.Gln183Lys
NC_000002.11:g.47637413C>A
NM_000251.1:c.547C>A
NM_000251.2:c.547C>A

Protein change:

Q117K

Links:

dbSNP: rs63750037

NCBI 1000 Genomes Browser:

rs63750037

Molecular consequence:

NM_000251.3:c.547C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.349C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Homo sapiens ribosomal protein S14 pseudogene 3, mRNA (cDNA clone IMAGE:6201343)
Homo sapiens ribosomal protein S14 pseudogene 3, mRNA (cDNA clone IMAGE:6201343)
gi|49116148|gb|BC072682.1|

Nucleotide
Cucurbita argyrosperma subsp. argyrosperma cultivar Calabaza pipiana chromosome ...
Cucurbita argyrosperma subsp. argyrosperma cultivar Calabaza pipiana chromosome 11, whole genome shotgun sequence
gi|2054009394|gb|CM032145.1||gnl|WG N|Carg_Chr11

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004828399	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004828399

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 2, 2023)

germline

clinical testing

PubMed (2)
[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

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, SCV004828399.1

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

Description

This missense variant replaces glutamine with lysine at codon 183 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 MSH2-related disorders in the literature. This variant has been identified in 1/30944 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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