NM_000251.3(MSH2):c.2074G>A (p.Gly692Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 2, 2020
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:: RCV000490901.7

Allele description [Variation Report for NM_000251.3(MSH2):c.2074G>A (p.Gly692Arg)]

NM_000251.3(MSH2):c.2074G>A (p.Gly692Arg)

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>A (p.Gly692Arg)

HGVS:

NC_000002.12:g.47476435G>A
NG_007110.2:g.78312G>A
NM_000251.3:c.2074G>AMANE SELECT
NM_001258281.1:c.1876G>A
NP_000242.1:p.Gly692Arg
NP_000242.1:p.Gly692Arg
NP_001245210.1:p.Gly626Arg
LRG_218t1:c.2074G>A
LRG_218:g.78312G>A
LRG_218p1:p.Gly692Arg
NC_000002.11:g.47703574G>A
NM_000251.1:c.2074G>A
NM_000251.2:c.2074G>A

Protein change:

G626R

Links:

dbSNP: rs63750232

NCBI 1000 Genomes Browser:

rs63750232

Molecular consequence:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580482	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 14, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10612836, 26951660, 28577310 Citation Link,
SCV000910480	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580482

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 14, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000910480

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 2, 2020)

germline

clinical testing

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

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

Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants.

Houlleberghs H, Dekker M, Lantermans H, Kleinendorst R, Dubbink HJ, Hofstra RM, Verhoef S, Te Riele H.

Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4128-33. doi: 10.1073/pnas.1520813113. Epub 2016 Mar 7.

PubMed [citation]

PMID:: 26951660
PMCID:: PMC4839441

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000580482.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.G692R variant (also known as c.2074G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2074. The glycine at codon 692 is replaced by arginine, an amino acid with dissimilar properties. A similar mutation, c.2074G>C, which leads to the same amino acid change, p.G692R, has been reported in a Portuguese family meeting Amsterdam I criteria (Isidro G et al. Hum Mut. 2000 Jan;15(1):116). The glycine at position 692 is in a well conserved region, close to the ATP binding domain and functional analysis of the yeast equivalent demonstrated 5% steady-state levels of wildtype MSH2 and a loss of interaction with all MSH2 partners. A variant was considered to have a significant defect if levels were <40% of wildtype MSH2 (Gammie AE et al. Genetics. 2007 Oct;177(2): 707-21). In addition, the c.2074G>C alteration has been classified as a likely pathogenic variant by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Furthermore, all internal cases with the c.2074G>C mutation meet Bethesda or Amsterdam criteria and cases for which tumor studies were available showed concordance (Ambry Internal Data). The c.2074G>A variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the available evidence, this variant is classified as a pathogenic mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000910480.3

#	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 glycine with arginine at codon 692 of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts DNA mismatch repair activity in a mouse embryonic stem cell-based assay (PMID: 26951660). While to our knowledge, this specific variant has not been reported in individuals affected with hereditary cancer in the literature, a different variant (c.2074G>C) resulting in the same amino acid change has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 10612836) and is considered to be disease-causing (ClinVar variation ID: 90878). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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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