NM_000251.3(MSH2):c.2030C>G (p.Thr677Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 30, 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:: RCV000462315.7

Allele description [Variation Report for NM_000251.3(MSH2):c.2030C>G (p.Thr677Arg)]

NM_000251.3(MSH2):c.2030C>G (p.Thr677Arg)

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.2030C>G (p.Thr677Arg)

HGVS:

NC_000002.12:g.47476391C>G
NG_007110.2:g.78268C>G
NM_000251.3:c.2030C>GMANE SELECT
NM_001258281.1:c.1832C>G
NP_000242.1:p.Thr677Arg
NP_000242.1:p.Thr677Arg
NP_001245210.1:p.Thr611Arg
LRG_218t1:c.2030C>G
LRG_218:g.78268C>G
LRG_218p1:p.Thr677Arg
NC_000002.11:g.47703530C>G
NM_000251.1:c.2030C>G
NM_000251.2:c.2030C>G

Protein change:

T611R

Links:

dbSNP: rs876660711

NCBI 1000 Genomes Browser:

rs876660711

Molecular consequence:

NM_000251.3:c.2030C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1832C>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
SCV000548317	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22086678, 27432916, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548317

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 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

Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing.

Bartley AN, Luthra R, Saraiya DS, Urbauer DL, Broaddus RR.

Cancer Prev Res (Phila). 2012 Feb;5(2):320-7. doi: 10.1158/1940-6207.CAPR-11-0288. Epub 2011 Nov 15.

PubMed [citation]

PMID:: 22086678
PMCID:: PMC3273660

DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics.

de Rosa N, Rodriguez-Bigas MA, Chang GJ, Veerapong J, Borras E, Krishnan S, Bednarski B, Messick CA, Skibber JM, Feig BW, Lynch PM, Vilar E, You YN.

J Clin Oncol. 2016 Sep 1;34(25):3039-46. doi: 10.1200/JCO.2016.66.6826. Epub 2016 Jul 18.

PubMed [citation]

PMID:: 27432916
PMCID:: PMC5012714

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548317.6

#	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 threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 677 of the MSH2 protein (p.Thr677Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 22086678, 27432916; Invitae). ClinVar contains an entry for this variant (Variation ID: 233888). 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: Oct 8, 2024

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