NM_000251.3(MSH2):c.118G>A (p.Gly40Ser) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 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:: RCV003997143.2

Allele description [Variation Report for NM_000251.3(MSH2):c.118G>A (p.Gly40Ser)]

NM_000251.3(MSH2):c.118G>A (p.Gly40Ser)

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.118G>A (p.Gly40Ser)

HGVS:

NC_000002.12:g.47403309G>A
NG_007110.2:g.5186G>A
NM_000251.3:c.118G>AMANE SELECT
NM_001258281.1:c.-30-51G>A
NP_000242.1:p.Gly40Ser
NP_000242.1:p.Gly40Ser
LRG_218t1:c.118G>A
LRG_218:g.5186G>A
LRG_218p1:p.Gly40Ser
NC_000002.11:g.47630448G>A
NM_000251.1:c.118G>A
NM_000251.2:c.118G>A
P43246:p.Gly40Ser

Protein change:

G40S

Links:

UniProtKB: P43246#VAR_043739; dbSNP: rs63751260

NCBI 1000 Genomes Browser:

rs63751260

Molecular consequence:

NM_001258281.1:c.-30-51G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004828914	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12792735, 26380806, 31386297, 31666926, 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004828914

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (6)
[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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene.

Yamada K, Zhong X, Kanazawa S, Koike J, Tsujita K, Hemmi H.

Oncol Rep. 2003 Jul-Aug;10(4):859-66.

PubMed [citation]

PMID:: 12792735

Total colectomy for multiple metachronous colon cancers in a patient with Lynch syndrome.

Kochi M, Shimomura M, Hinoi T, Niitsu H, Yano T, Mukai S, Sawada H, Miguchi M, Saito Y, Adachi T, Ishizaki Y, Egi H, Ohdan H.

Surg Case Rep. 2015 Dec;1(1):78. doi: 10.1186/s40792-015-0081-x.

PubMed [citation]

PMID:: 26380806
PMCID:: PMC4564456

See all PubMed Citations (6)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004828914.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces glycine with serine at codon 40 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 12792735, 26380806), bile duct cancer (PMID: 31666926), and unspecified cancer (PMID: 31386297). This variant has been identified in 2/227630 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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