NM_000251.3(MSH2):c.1862G>T (p.Arg621Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 25, 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:: RCV000205853.9

Allele description [Variation Report for NM_000251.3(MSH2):c.1862G>T (p.Arg621Leu)]

NM_000251.3(MSH2):c.1862G>T (p.Arg621Leu)

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.1862G>T (p.Arg621Leu)

HGVS:

NC_000002.12:g.47475127G>T
NG_007110.2:g.77004G>T
NM_000251.3:c.1862G>TMANE SELECT
NM_001258281.1:c.1664G>T
NP_000242.1:p.Arg621Leu
NP_000242.1:p.Arg621Leu
NP_001245210.1:p.Arg555Leu
LRG_218t1:c.1862G>T
LRG_218:g.77004G>T
LRG_218p1:p.Arg621Leu
NC_000002.11:g.47702266G>T
NM_000251.1:c.1862G>T
NM_000251.2:c.1862G>T

Protein change:

R555L

Links:

dbSNP: rs759263820

NCBI 1000 Genomes Browser:

rs759263820

Molecular consequence:

NM_000251.3:c.1862G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1664G>T - 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
SCV000261128	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21520333, 30702970, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000261128

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

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

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process.

Salvador MU, Truelson MRF, Mason C, Souders B, LaDuca H, Dougall B, Black MH, Fulk K, Profato J, Gutierrez S, Jasperson K, Tippin-Davis B, Lu HM, Gray P, Shah S, Chao EC, Ghahramani N, Landsverk M, Gau CL, Chen D, Pronold M.

J Clin Oncol. 2019 Mar 10;37(8):647-657. doi: 10.1200/JCO.18.00696. Epub 2019 Jan 31.

PubMed [citation]

PMID:: 30702970
PMCID:: PMC6494248

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000261128.9

#	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 leucine, which is neutral and non-polar, at codon 621 of the MSH2 protein (p.Arg621Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Lynch syndrome (PMID: 21520333, 30702970; Invitae). ClinVar contains an entry for this variant (Variation ID: 218040). 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%. 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: Jun 9, 2024

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