NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 14, 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:: RCV000772137.8

Allele description [Variation Report for NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)]

NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)

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.2075G>A (p.Gly692Glu)

HGVS:

NC_000002.12:g.47476436G>A
NG_007110.2:g.78313G>A
NM_000251.3:c.2075G>AMANE SELECT
NM_001258281.1:c.1877G>A
NP_000242.1:p.Gly692Glu
NP_000242.1:p.Gly692Glu
NP_001245210.1:p.Gly626Glu
LRG_218t1:c.2075G>A
LRG_218:g.78313G>A
LRG_218p1:p.Gly692Glu
NC_000002.11:g.47703575G>A
NM_000251.1:c.2075G>A
NM_000251.2:c.2075G>A

Protein change:

G626E

Links:

dbSNP: rs63751432

NCBI 1000 Genomes Browser:

rs63751432

Molecular consequence:

NM_000251.3:c.2075G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258281.1:c.1877G>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
SCV000905240	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002726728	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 21, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17531815, 29887214 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000905240

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 14, 2023)

germline

clinical testing

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

SCV002726728

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 21, 2021)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]

PMID:: 17531815

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000905240.4

#	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 glutamic acid at codon 692 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer with tumors showing microsatellite instability and lack of MSH2 and MSH6 expression (http://www.umd.be/MSH2/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same position (p.Gly692Arg, p.Gly692Trp, p.Gly692Val) are known to be disease-causing (Clinvar variation ID: 428477, 90878, 428464, 90880), suggesting the importance of glycine residue at this amino acid position. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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 Ambry Genetics, SCV002726728.2

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

Description

The p.G692E variant (also known as c.2075G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2075. The glycine at codon 692 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in a patient with trifocal colon cancer at age 41 and loss of MSH2/MSH6 on IHC (UMD-MSH2 database). Based on internal structural analysis this alteration destabilizes the ATPase domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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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