NM_000251.3(MSH2):c.2267C>G (p.Thr756Ser) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 17, 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:: RCV004000793.2

Allele description [Variation Report for NM_000251.3(MSH2):c.2267C>G (p.Thr756Ser)]

NM_000251.3(MSH2):c.2267C>G (p.Thr756Ser)

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.2267C>G (p.Thr756Ser)

HGVS:

NC_000002.12:g.47478328C>G
NG_007110.2:g.80205C>G
NM_000251.3:c.2267C>GMANE SELECT
NM_001258281.1:c.2069C>G
NP_000242.1:p.Thr756Ser
NP_000242.1:p.Thr756Ser
NP_001245210.1:p.Thr690Ser
LRG_218t1:c.2267C>G
LRG_218:g.80205C>G
LRG_218p1:p.Thr756Ser
NC_000002.11:g.47705467C>G
NM_000251.1:c.2267C>G
NM_000251.2:c.2267C>G

Protein change:

T690S

Links:

dbSNP: rs372383829

NCBI 1000 Genomes Browser:

rs372383829

Molecular consequence:

NM_000251.3:c.2267C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2069C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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P-loop containing nucleoside triphosphate hydrolases superfamily protein [Arabid...
P-loop containing nucleoside triphosphate hydrolases superfamily protein [Arabidopsis thaliana]
gi|15240788|ref|NP_201564.1|

Protein
Phlda2 pleckstrin homology-like domain, family A, member 2 [Rattus norvegicus]
Phlda2 pleckstrin homology-like domain, family A, member 2 [Rattus norvegicus]
Gene ID:293637

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004825825	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27443514, 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004825825

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 17, 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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort.

Ring KL, Bruegl AS, Allen BA, Elkin EP, Singh N, Hartman AR, Daniels MS, Broaddus RR.

Mod Pathol. 2016 Nov;29(11):1381-1389. doi: 10.1038/modpathol.2016.135. Epub 2016 Jul 22.

PubMed [citation]

PMID:: 27443514
PMCID:: PMC5541389

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 All of Us Research Program, National Institutes of Health, SCV004825825.1

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

Description

This missense variant replaces threonine with serine at codon 756 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 8/282812 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		1	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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