NM_000251.3(MSH2):c.2479G>A (p.Gly827Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 14, 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:: RCV001071073.10

Allele description [Variation Report for NM_000251.3(MSH2):c.2479G>A (p.Gly827Arg)]

NM_000251.3(MSH2):c.2479G>A (p.Gly827Arg)

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.2479G>A (p.Gly827Arg)

HGVS:

NC_000002.12:g.47480716G>A
NG_007110.2:g.82593G>A
NM_000251.3:c.2479G>AMANE SELECT
NM_001258281.1:c.2281G>A
NP_000242.1:p.Gly827Arg
NP_001245210.1:p.Gly761Arg
LRG_218t1:c.2479G>A
LRG_218:g.82593G>A
NC_000002.11:g.47707855G>A
NM_000251.1:c.2479G>A
NM_000251.2:c.2479G>A

Protein change:

G761R

Links:

dbSNP: rs63750478

NCBI 1000 Genomes Browser:

rs63750478

Molecular consequence:

NM_000251.3:c.2479G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001236357	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32933947, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001236357

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 14, 2023)

germline

clinical testing

PubMed (3)
[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

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.

Grant RC, Denroche R, Jang GH, Nowak KM, Zhang A, Borgida A, Holter S, Topham JT, Wilson J, Dodd A, Jang R, Prince R, Karasinska JM, Schaeffer DF, Wang Y, Zogopoulos G, Berry S, Simeone D, Renouf DJ, Notta F, O'Kane G, Knox J, et al.

Gut. 2021 Oct;70(10):1894-1903. doi: 10.1136/gutjnl-2020-320730. Epub 2020 Sep 15.

PubMed [citation]

PMID:: 32933947

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001236357.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 827 of the MSH2 protein (p.Gly827Arg). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly827 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 32933947), which suggests that this may be a clinically significant amino acid residue. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 863985). This missense change has been observed in individual(s) with uterine cancer (Invitae).

#	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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