NM_000251.3(MSH2):c.792+5A>G AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 20, 2021
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:: RCV000440249.13

Allele description [Variation Report for NM_000251.3(MSH2):c.792+5A>G]

NM_000251.3(MSH2):c.792+5A>G

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.792+5A>G

HGVS:

NC_000002.12:g.47412565A>G
NG_007110.2:g.14442A>G
NM_000251.3:c.792+5A>GMANE SELECT
NM_001258281.1:c.594+5A>G
LRG_218t1:c.792+5A>G
LRG_218:g.14442A>G
NC_000002.11:g.47639704A>G
NM_000251.1:c.792+5A>G
NM_000251.2:c.792+5A>G

Links:

dbSNP: rs267607935

NCBI 1000 Genomes Browser:

rs267607935

Molecular consequence:

NM_000251.3:c.792+5A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258281.1:c.594+5A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000513654	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Aug 7, 2017)	germline	clinical testing	Citation Link,
SCV000696283	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Dec 20, 2021)	germline	clinical testing	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

SCV000513654

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Aug 7, 2017)

germline

clinical testing

Citation Link,

SCV000696283

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Dec 20, 2021)

germline

clinical testing

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF.

Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7. Epub 2004 Nov 1.

PubMed [citation]

PMID:: 15520370
PMCID:: PMC528777

Details of each submission

From GeneDx, SCV000513654.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696283.2

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

Description

Variant summary: MSH2 c.792+5A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251112 control chromosomes, however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.792+5A>G has been reported in the literature in individuals affected with Colorectal Cancer (example: Fearnhead_2004). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one as uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Nov 3, 2024

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