NM_000251.3(MSH2):c.2267C>G (p.Thr756Ser) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 19, 2024
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:: RCV000464961.9

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]

Condition(s)

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

Recent activity

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protein CC2D2B isoform 1 [Homo sapiens]
protein CC2D2B isoform 1 [Homo sapiens]
gi|229577352|ref|NP_001153219.1|

Protein
Mus musculus centromere protein Q, mRNA (cDNA clone MGC:27944 IMAGE:3588374), co...
Mus musculus centromere protein Q, mRNA (cDNA clone MGC:27944 IMAGE:3588374), complete cds
gi|17391240|gb|BC018524.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548300	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27443514, 33357406, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548300

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

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

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 Invitae, SCV000548300.10

#	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 threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 756 of the MSH2 protein (p.Thr756Ser). This variant is present in population databases (rs372383829, gnomAD 0.02%). This missense change has been observed in individual(s) with endometrial carcinoma (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 408544). 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 with a negative predictive value of 80%. 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 9, 2024

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