NM_000251.3(MSH2):c.560T>C (p.Leu187Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000581973.7

Allele description [Variation Report for NM_000251.3(MSH2):c.560T>C (p.Leu187Pro)]

NM_000251.3(MSH2):c.560T>C (p.Leu187Pro)

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.560T>C (p.Leu187Pro)

HGVS:

NC_000002.12:g.47410287T>C
NG_007110.2:g.12164T>C
NM_000251.3:c.560T>CMANE SELECT
NM_001258281.1:c.362T>C
NP_000242.1:p.Leu187Pro
NP_000242.1:p.Leu187Pro
NP_001245210.1:p.Leu121Pro
LRG_218t1:c.560T>C
LRG_218:g.12164T>C
LRG_218p1:p.Leu187Pro
NC_000002.11:g.47637426T>C
NM_000251.1:c.560T>C
NM_000251.2:c.560T>C
P43246:p.Leu187Pro

Protein change:

L121P

Links:

UniProtKB: P43246#VAR_043753; dbSNP: rs63751444

NCBI 1000 Genomes Browser:

rs63751444

Molecular consequence:

NM_000251.3:c.560T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.362T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000690118	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 9, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15849733, 17101317, 17192056, 20176959, 28422960, 30998989, 33357406, 25741868
SCV001186319	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15849733, 16327991, 17101317, 20176959, 28422960 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000690118

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 9, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001186319

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 3, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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	1	not provided	clinical testing

Citations

PubMed

The use of microsatellite instability, immunohistochemistry and other variables in determining the clinical significance of MLH1 and MSH2 unclassified variants in Lynch syndrome.

Lucci-Cordisco E, Boccuto L, Neri G, Genuardi M.

Cancer Biomark. 2006;2(1-2):11-27. Review.

PubMed [citation]

PMID:: 17192056

Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.

Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, Duval A, Coulet F, Muleris M.

Gastroenterology. 2019 Aug;157(2):421-431. doi: 10.1053/j.gastro.2019.03.071. Epub 2019 Apr 15.

PubMed [citation]

PMID:: 30998989

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000690118.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces leucine with proline at codon 187 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 has deficient DNA repair and tolerance to DNA damaging agents (PMID: 17101317, 20176959, 28422960, 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17192056). 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 Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV001186319.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The p.L187P pathogenic mutation (also known as c.560T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 560. The leucine at codon 187 is replaced by proline, an amino acid with similar properties. This mutation has been reported in families meeting Bethesda or Amsterdam criteria and segregated with disease in one family with Muire-Torre phenotype (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53). Published structural analysis suggests that this alteration (L187P) structurally destabalizes the MSH2 protein resulting in reduced binding to MSH3 and MSH6 (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In addition, functional assays have shown that the L187P protein is MMR deficient (Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53; Ollila S et al. Gastroenterology 2006 Nov;131:1408-17; Martinez SL et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107:5070-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 20, 2024

ClinVar

Relating variation to medicine