NM_000251.3(MSH2):c.1861C>G (p.Arg621Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 7, 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:: RCV000465743.11

Allele description [Variation Report for NM_000251.3(MSH2):c.1861C>G (p.Arg621Gly)]

NM_000251.3(MSH2):c.1861C>G (p.Arg621Gly)

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.1861C>G (p.Arg621Gly)

HGVS:

NC_000002.12:g.47475126C>G
NG_007110.2:g.77003C>G
NM_000251.3:c.1861C>GMANE SELECT
NM_001258281.1:c.1663C>G
NP_000242.1:p.Arg621Gly
NP_000242.1:p.Arg621Gly
NP_001245210.1:p.Arg555Gly
LRG_218t1:c.1861C>G
LRG_218:g.77003C>G
LRG_218p1:p.Arg621Gly
NC_000002.11:g.47702265C>G
NM_000251.1:c.1861C>G
NM_000251.2:c.1861C>G

Protein change:

R555G

Links:

dbSNP: rs63750508

NCBI 1000 Genomes Browser:

rs63750508

Molecular consequence:

NM_000251.3:c.1861C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1663C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23729658, 33357406, 30702970, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 7, 2023)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families.

Grandval P, Fabre AJ, Gaildrat P, Baert-Desurmont S, Buisine MP, Ferrari A, Wang Q, Béroud C, Olschwang S.

Database (Oxford). 2013 May 31;2013:bat036. doi: 10.1093/database/bat036. Print 2013.

PubMed [citation]

PMID:: 23729658
PMCID:: PMC3668602

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548260.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 621 of the MSH2 protein (p.Arg621Gly). This variant is present in population databases (rs63750508, gnomAD 0.0009%). This missense change has been observed in individuals with Lynch syndrome (PMID: 23729658; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 408524). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. This variant disrupts the p.Arg621 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30702970; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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

Last Updated: Sep 29, 2024

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