NM_000249.4(MLH1):c.790+1G>A AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 21, 2024
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:: RCV000524316.15

Allele description [Variation Report for NM_000249.4(MLH1):c.790+1G>A]

NM_000249.4(MLH1):c.790+1G>A

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.790+1G>A

HGVS:

NC_000003.12:g.37014545G>A
NG_007109.2:g.26196G>A
NM_000249.4:c.790+1G>AMANE SELECT
NM_001167617.3:c.496+1G>A
NM_001167618.3:c.67+1G>A
NM_001167619.3:c.67+1G>A
NM_001258271.2:c.790+1G>A
NM_001258273.2:c.67+1G>A
NM_001258274.3:c.67+1G>A
NM_001354615.2:c.67+1G>A
NM_001354616.2:c.67+1G>A
NM_001354617.2:c.67+1G>A
NM_001354618.2:c.67+1G>A
NM_001354619.2:c.67+1G>A
NM_001354620.2:c.496+1G>A
NM_001354621.2:c.-140+2446G>A
NM_001354622.2:c.-140+1G>A
NM_001354623.2:c.-140+1G>A
NM_001354624.2:c.-37+1G>A
NM_001354625.2:c.-37+1G>A
NM_001354626.2:c.-37+1G>A
NM_001354627.2:c.-37+1G>A
NM_001354628.2:c.790+1G>A
NM_001354629.2:c.691+1G>A
NM_001354630.2:c.790+1G>A
LRG_216t1:c.790+1G>A
LRG_216:g.26196G>A
NC_000003.11:g.37056036G>A
NM_000249.3:c.790+1G>A

Links:

dbSNP: rs267607789

NCBI 1000 Genomes Browser:

rs267607789

Molecular consequence:

NM_001354621.2:c.-140+2446G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.790+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167617.3:c.496+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167618.3:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167619.3:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258271.2:c.790+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258273.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258274.3:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354615.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354616.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354617.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354618.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354619.2:c.67+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354620.2:c.496+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354622.2:c.-140+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354623.2:c.-140+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354624.2:c.-37+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354625.2:c.-37+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354626.2:c.-37+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354627.2:c.-37+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354628.2:c.790+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354629.2:c.691+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354630.2:c.790+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284075	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11524701, 15849733, 15955785, 17054581, 20937110, 24710284, 11781295, 16395668, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284075

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 21, 2024)

germline

clinical testing

PubMed (9)
[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

The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.

Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh Vockley C, Kubly V, Nelson H, Michels VV, Thibodeau SN.

Am J Hum Genet. 2001 Oct;69(4):780-90. Epub 2001 Aug 24. Erratum in: Am J Hum Genet 2001 Nov;69(5):1160.

PubMed [citation]

PMID:: 11524701
PMCID:: PMC1226064

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000284075.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change affects a donor splice site in intron 9 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome and colorectal cancer (PMID: 11524701, 15849733, 15955785, 17054581, 20937110, 24710284). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 90356). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects MLH1 function (PMID: 11781295). Studies have shown that disruption of this splice site results in skipping of exons 9-10, but is expected to preserve the integrity of the reading-frame (PMID: 16395668). For these reasons, this variant has been classified as 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: Apr 15, 2024

ClinVar

Relating variation to medicine