NM_000251.3(MSH2):c.446G>A (p.Gly149Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 15, 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:: RCV000821319.6

Allele description [Variation Report for NM_000251.3(MSH2):c.446G>A (p.Gly149Asp)]

NM_000251.3(MSH2):c.446G>A (p.Gly149Asp)

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.446G>A (p.Gly149Asp)

HGVS:

NC_000002.12:g.47410173G>A
NG_007110.2:g.12050G>A
NM_000251.3:c.446G>AMANE SELECT
NM_001258281.1:c.248G>A
NP_000242.1:p.Gly149Asp
NP_000242.1:p.Gly149Asp
NP_001245210.1:p.Gly83Asp
LRG_218t1:c.446G>A
LRG_218:g.12050G>A
LRG_218p1:p.Gly149Asp
NC_000002.11:g.47637312G>A
NM_000251.1:c.446G>A
NM_000251.2:c.446G>A

Protein change:

G149D

Links:

dbSNP: rs587779162

NCBI 1000 Genomes Browser:

rs587779162

Molecular consequence:

NM_000251.3:c.446G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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HECW2 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 [Pan trogl...
HECW2 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 [Pan troglodytes]
Gene ID:459844

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000962073	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18383312, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000962073

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 15, 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

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).

Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM.

Hum Mutat. 2008 Jun;29(6):852-60. doi: 10.1002/humu.20735.

PubMed [citation]

PMID:: 18383312

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 Invitae, SCV000962073.4

#	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 aspartic acid, which is acidic and polar, at codon 149 of the MSH2 protein (p.Gly149Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18383312). ClinVar contains an entry for this variant (Variation ID: 91099). 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%. 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.

#	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 17, 2024

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