NM_000251.3(MSH2):c.518T>C (p.Leu173Pro) AND Lynch syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 5, 2024
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:: RCV003997177.2

Allele description [Variation Report for NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)]

NM_000251.3(MSH2):c.518T>C (p.Leu173Pro)

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.518T>C (p.Leu173Pro)

HGVS:

NC_000002.12:g.47410245T>C
NG_007110.2:g.12122T>C
NM_000251.3:c.518T>CMANE SELECT
NM_001258281.1:c.320T>C
NP_000242.1:p.Leu173Pro
NP_000242.1:p.Leu173Pro
NP_001245210.1:p.Leu107Pro
LRG_218t1:c.518T>C
LRG_218:g.12122T>C
LRG_218p1:p.Leu173Pro
NC_000002.11:g.47637384T>C
NM_000251.1:c.518T>C
NM_000251.2:c.518T>C
P43246:p.Leu173Pro

Protein change:

L107P

Links:

UniProtKB: P43246#VAR_043751; dbSNP: rs63750070

NCBI 1000 Genomes Browser:

rs63750070

Molecular consequence:

NM_000251.3:c.518T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.320T>C - 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
SCV004822610	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15849733, 17101317, 17594722, 18951462, 33357406, 33422027, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004822610

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Feb 5, 2024)

germline

clinical testing

PubMed (7)
[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

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomäki P, Mangold E, de la Chapelle A, Greenblatt M, Nyström M.

Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22.

PubMed [citation]

PMID:: 17101317

See all PubMed Citations (7)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004822610.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces leucine with proline at codon 173 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). Functional studies have shown that this variant causes significantly decreased mismatch repair activity compared to wild type protein (PMID: 17101317, 17594722, 18951462), and that the variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17594722, 18951462, 33422027). A different variant affecting the same codon, c.518T>G (p.Leu173Arg), is considered to be disease-causing (ClinVar variation ID: 91122), suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Oct 8, 2024

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