NM_000251.3(MSH2):c.2074G>T (p.Gly692Trp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 20, 2020
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:: RCV001209603.8

Allele description [Variation Report for NM_000251.3(MSH2):c.2074G>T (p.Gly692Trp)]

NM_000251.3(MSH2):c.2074G>T (p.Gly692Trp)

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.2074G>T (p.Gly692Trp)

HGVS:

NC_000002.12:g.47476435G>T
NG_007110.2:g.78312G>T
NM_000251.3:c.2074G>TMANE SELECT
NM_001258281.1:c.1876G>T
NP_000242.1:p.Gly692Trp
NP_000242.1:p.Gly692Trp
NP_001245210.1:p.Gly626Trp
LRG_218t1:c.2074G>T
LRG_218:g.78312G>T
LRG_218p1:p.Gly692Trp
NC_000002.11:g.47703574G>T
NM_000251.1:c.2074G>T
NM_000251.2:c.2074G>T

Protein change:

G626W

Links:

dbSNP: rs63750232

NCBI 1000 Genomes Browser:

rs63750232

Molecular consequence:

NM_000251.3:c.2074G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1876G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X2, mR...
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X2, mRNA
gi|2462550236|ref|XM_054313665.1|

Nucleotide
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X7, mR...
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X7, mRNA
gi|2217307041|ref|XM_047434482.1|

Nucleotide
DUF484 domain-containing protein [Cronobacter sakazakii]
DUF484 domain-containing protein [Cronobacter sakazakii]
gi|490523010|ref|WP_004388420.1|

Protein
Habenaria lithophila voucher Bytebier 2185 small subunit ribosomal RNA gene, par...
Habenaria lithophila voucher Bytebier 2185 small subunit ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8S ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and large subunit ribosomal RNA gene, partial sequence
gi|1844067969|gb|MT500589.1|

Nucleotide
Klebsiella variicola strain Kpngiani7132485 genome assembly, contig: .25052_8_28...
Klebsiella variicola strain Kpngiani7132485 genome assembly, contig: .25052_8_28_trimmed.34, whole genome shotgun sequence
gi|1784638448|emb|CACSDT010000034.1

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001381046	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 20, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10612836, 12624141, 23454724, 23729658, 28577310, 29212164, 28135145, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001381046

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 20, 2020)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Four novel MSH2 / MLH1 gene mutations in portuguese HNPCC families.

Isidro G, Veiga I, Matos P, Almeida S, Bizarro S, Marshall B, Baptista M, Leite J, Regateiro F, Soares J, Castedo S, Boavida MG.

Hum Mutat. 2000 Jan;15(1):116.

PubMed [citation]

PMID:: 10612836

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001381046.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612836, 12624141, 23454724, 23729658, 28577310, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with Lynch syndrome in a family (external communication). Also, it has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 28135145, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 428464). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 692 of the MSH2 protein (p.Gly692Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan.

#	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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