NM_000251.3(MSH2):c.2798C>T (p.Thr933Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 5, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000216013.19

Allele description [Variation Report for NM_000251.3(MSH2):c.2798C>T (p.Thr933Ile)]

NM_000251.3(MSH2):c.2798C>T (p.Thr933Ile)

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.2798C>T (p.Thr933Ile)

Other names:

p.T933I:ACT>ATT

HGVS:

NC_000002.12:g.47482942C>T
NG_007110.2:g.84819C>T
NM_000251.3:c.2798C>TMANE SELECT
NM_001258281.1:c.2600C>T
NP_000242.1:p.Thr933Ile
NP_000242.1:p.Thr933Ile
NP_001245210.1:p.Thr867Ile
LRG_218t1:c.2798C>T
LRG_218:g.84819C>T
LRG_218p1:p.Thr933Ile
NC_000002.11:g.47710081C>T
NM_000251.1:c.2798C>T
NM_000251.2:c.2798C>T

Protein change:

T867I

Links:

dbSNP: rs587779968

NCBI 1000 Genomes Browser:

rs587779968

Molecular consequence:

NM_000251.3:c.2798C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.2600C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278376	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely benign (Aug 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33357406, 33471991 Citation Link,
SCV000537579	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002534505	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 13, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278376

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely benign
(Aug 29, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000537579

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 5, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002534505

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 13, 2021)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

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	1	not provided	clinical testing, curation

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000278376.6

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

Description

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000537579.6

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

Description

This missense variant replaces threonine with isoleucine at codon 933 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/279118 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002534505.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	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: Apr 20, 2024

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