NM_000251.3(MSH2):c.1962C>G (p.Asp654Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 5, 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:: RCV000219670.6

Allele description [Variation Report for NM_000251.3(MSH2):c.1962C>G (p.Asp654Glu)]

NM_000251.3(MSH2):c.1962C>G (p.Asp654Glu)

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.1962C>G (p.Asp654Glu)

HGVS:

NC_000002.12:g.47475227C>G
NG_007110.2:g.77104C>G
NM_000251.3:c.1962C>GMANE SELECT
NM_001258281.1:c.1764C>G
NP_000242.1:p.Asp654Glu
NP_000242.1:p.Asp654Glu
NP_001245210.1:p.Asp588Glu
LRG_218t1:c.1962C>G
LRG_218:g.77104C>G
LRG_218p1:p.Asp654Glu
NC_000002.11:g.47702366C>G
NM_000251.1:c.1962C>G
NM_000251.2:c.1962C>G

Protein change:

D588E

Links:

dbSNP: rs751939698

NCBI 1000 Genomes Browser:

rs751939698

Molecular consequence:

NM_000251.3:c.1962C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1764C>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Homo sapiens cubilin (intrinsic factor-cobalamin receptor) (CUBN), mRNA
Homo sapiens cubilin (intrinsic factor-cobalamin receptor) (CUBN), mRNA
gi|4557502|ref|NM_001081.1|

Nucleotide
thop1 thimet oligopeptidase 1 [Danio rerio]
thop1 thimet oligopeptidase 1 [Danio rerio]
Gene ID:436628

Gene
snx17 sorting nexin 17 [Danio rerio]
snx17 sorting nexin 17 [Danio rerio]
Gene ID:568263

Gene
cmpk cytidylate kinase [Danio rerio]
cmpk cytidylate kinase [Danio rerio]
Gene ID:406383

Gene
dpysl5a dihydropyrimidinase like 5a [Danio rerio]
dpysl5a dihydropyrimidinase like 5a [Danio rerio]
Gene ID:324416

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000275566	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002534431	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Feb 26, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275566

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 5, 2022)

germline

clinical testing

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

Citation Link,

SCV002534431

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Feb 26, 2022)

germline

curation

Citation Link

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, 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

Details of each submission

From Ambry Genetics, SCV000275566.7

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

Description

The p.D654E variant (also known as c.1962C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1962. The aspartic acid at codon 654 is replaced by glutamic acid, an amino acid with highly similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV002534431.1

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

#	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 29, 2024

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