NM_000251.3(MSH2):c.97A>C (p.Thr33Pro) AND Lynch syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 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:: RCV003997185.2

Allele description [Variation Report for NM_000251.3(MSH2):c.97A>C (p.Thr33Pro)]

NM_000251.3(MSH2):c.97A>C (p.Thr33Pro)

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.97A>C (p.Thr33Pro)

HGVS:

NC_000002.12:g.47403288A>C
NG_007110.2:g.5165A>C
NM_000251.3:c.97A>CMANE SELECT
NM_001258281.1:c.-30-72A>C
NP_000242.1:p.Thr33Pro
NP_000242.1:p.Thr33Pro
LRG_218t1:c.97A>C
LRG_218:g.5165A>C
LRG_218p1:p.Thr33Pro
NC_000002.11:g.47630427A>C
NM_000251.1:c.97A>C
NM_000251.2:c.97A>C
P43246:p.Thr33Pro
p.T33P

Protein change:

T33P

Links:

UniProtKB: P43246#VAR_043738; dbSNP: rs63751107

NCBI 1000 Genomes Browser:

rs63751107

Molecular consequence:

NM_001258281.1:c.-30-72A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000251.3:c.97A>C - 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
SCV004826360	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16885385, 17101317, 20176959, 25559809, 30998989, 32634176, 33357406, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004826360

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (8)
[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	12	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.

Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, La Jeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, Penzone P, Lombardi J, Dunn P, Cohn DE, Copeland L, Eaton L, Fowler J, Lewandowski G, Vaccarello L, Bell J, et al.

Cancer Res. 2006 Aug 1;66(15):7810-7.

PubMed [citation]

PMID:: 16885385

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomäki P, Mangold E, de la Chapelle A, Greenblatt M, Nyström M.

Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22.

PubMed [citation]

PMID:: 17101317

See all PubMed Citations (8)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004826360.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces threonine with proline at codon 33 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). Functional studies reported this variant as partially functional in mismatch repair assay in vitro (PMID: 17101317) and in yeast (PMID: 20176959). This variant is functional in a methylation tolerance assay (PMID: 30998989) and 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 rectal cancer (PMID: 25559809) and at least two individuals affected with endometrial cancer (PMID: 16885385, 17101317, 32634176). This variant has been identified in 16/254182 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		12	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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