NM_000251.3(MSH2):c.97A>C (p.Thr33Pro) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 12, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000236043.11

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712785	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 31, 2019)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 22949387, 25559809, 20176959, 21120944, 18951462, 17101317, 16237223, 16885385, 18383312, 24033266
SCV002511445	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 12, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16237223, 16885385, 20176959, 25559809, 17101317, 26580448, 30998989, 31391288, 32634176, 33357406 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712785

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 31, 2019)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002511445

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 12, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV.

Hum Mutat. 2013 Jan;34(1):255-65. doi: 10.1002/humu.22214. Epub 2012 Oct 22.

PubMed [citation]

PMID:: 22949387
PMCID:: PMC4318556

Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.

Kansikas M, Kariola R, Nyström M.

Hum Mutat. 2011 Jan;32(1):107-15. doi: 10.1002/humu.21409.

PubMed [citation]

PMID:: 21120944
PMCID:: PMC3058133

See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712785.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

The p.Thr33Pro variant in MSH2 has been reported in 4 individuals with Lynch Syndrome-related cancers (Hedge 2005, Hampel 2006, Ollila 2006, Chubb 2015). Functional studies (microsatellite instability, immunohistochemistry, mismatch repair, expression and interaction assays) provide conflicting evidence on whether the p.Thr33Pro variant impacts protein function (Ollila 2006, Ollila 2008, Kansikas 2011, Martinez 2010). This variant has also been identified in 4/32028 Latino chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr33Pro variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107811.2). In summary, the clinical significance of the p.Thr33Pro variant is uncertain.

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511445.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: MSH2 c.97A>C (p.Thr33Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 222782 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (6.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.97A>C has been reported in the literature in individuals affected with Lynch Syndrome, endometrial cancer and colorectal cancer (Hegde_2005, Hampel_2006, Ollila_2006, Chubb_2015, Li_2020, Singh_2020), without strong evidence for causality. Several publications have reported functional studies of the variant showing: normal interaction with MSH6 but decreased in vitro MMR activity (Ollila_2006), weak MMR defect (Martinez_2010), while other pubications reported the variant to be neutral via assays that measured proportions of cells that undergo death following exposure to a methylating agent (Bouvet_2019) and in human cell line models in which MSH2 deletion was complemented by libraries of variants comprising nearly every possible MSH2 missense allele (Jia_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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: Sep 16, 2024

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