NM_000249.4(MLH1):c.589-1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 3, 2022
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:: RCV002356902.3

Allele description [Variation Report for NM_000249.4(MLH1):c.589-1G>A]

NM_000249.4(MLH1):c.589-1G>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.589-1G>A

HGVS:

NC_000003.12:g.37012010G>A
NG_007109.2:g.23661G>A
NM_000249.4:c.589-1G>AMANE SELECT
NM_001167617.3:c.295-1G>A
NM_001167618.3:c.-135-1G>A
NM_001167619.3:c.-135-1G>A
NM_001258271.2:c.589-1G>A
NM_001258273.2:c.-135-1G>A
NM_001258274.3:c.-135-1G>A
NM_001354615.2:c.-135-1G>A
NM_001354616.2:c.-135-1G>A
NM_001354617.2:c.-135-1G>A
NM_001354618.2:c.-135-1G>A
NM_001354619.2:c.-135-1G>A
NM_001354620.2:c.295-1G>A
NM_001354621.2:c.-228-1G>A
NM_001354622.2:c.-341-1G>A
NM_001354623.2:c.-341-1G>A
NM_001354624.2:c.-238-1G>A
NM_001354625.2:c.-238-1G>A
NM_001354626.2:c.-238-1G>A
NM_001354627.2:c.-238-1G>A
NM_001354628.2:c.589-1G>A
NM_001354629.2:c.490-1G>A
NM_001354630.2:c.589-1G>A
LRG_216t1:c.589-1G>A
LRG_216:g.23661G>A
NC_000003.11:g.37053501G>A
NM_000249.3:c.589-1G>A

Links:

dbSNP: rs587779027

NCBI 1000 Genomes Browser:

rs587779027

Molecular consequence:

NM_000249.4:c.589-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167617.3:c.295-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167618.3:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167619.3:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258271.2:c.589-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258273.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258274.3:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354615.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354616.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354617.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354618.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354619.2:c.-135-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354620.2:c.295-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354621.2:c.-228-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354622.2:c.-341-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354623.2:c.-341-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354624.2:c.-238-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354625.2:c.-238-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354626.2:c.-238-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354627.2:c.-238-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354628.2:c.589-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354629.2:c.490-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354630.2:c.589-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV002653164	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 3, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002653164

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 3, 2022)

germline

clinical testing

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

Details of each submission

From Ambry Genetics, SCV002653164.3

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

Description

The c.589-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MLH1 gene. Another alteration impacting the same acceptor site (c.589-2A>G) has been shown to have a similar impact on splicing and has been reported in numerous Lynch syndrome families to date (Luce MC et al. Gastroenterology. 1995 Oct;109(4):1368-74; Viel A et al. Community Genet. 1998;1(4):229-36; Capozzi E et al. Eur. J. Cancer. 1999 Feb;35(2):289-95; Syngal S et al. JAMA. 1999 Jul 21;282(3):247-53; Casey G et al. JAMA. 2005 Feb 16;293(7):799-809; DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5(5):553-569), and RNA studies have demonstrated that the c.589-2A>G alteration activates a cryptic acceptor site resulting in a transcript with a 4 base pair deletion, which is predicted to lead to a translational frameshift (Ambry internal data; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing 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

Last Updated: Jun 9, 2024

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