NM_000249.4(MLH1):c.1039-1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 28, 2023
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:: RCV004031329.1

Allele description [Variation Report for NM_000249.4(MLH1):c.1039-1G>C]

NM_000249.4(MLH1):c.1039-1G>C

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.1039-1G>C

HGVS:

NC_000003.12:g.37025636G>C
NG_007109.2:g.37287G>C
NM_000249.4:c.1039-1G>CMANE SELECT
NM_001167617.3:c.745-1G>C
NM_001167618.3:c.316-1G>C
NM_001167619.3:c.316-1G>C
NM_001258271.2:c.1039-1G>C
NM_001258273.2:c.316-1G>C
NM_001258274.3:c.316-1G>C
NM_001354615.2:c.316-1G>C
NM_001354616.2:c.316-1G>C
NM_001354617.2:c.316-1G>C
NM_001354618.2:c.316-1G>C
NM_001354619.2:c.316-1G>C
NM_001354620.2:c.745-1G>C
NM_001354621.2:c.16-1G>C
NM_001354622.2:c.16-1G>C
NM_001354623.2:c.16-1G>C
NM_001354624.2:c.-36-1G>C
NM_001354625.2:c.-36-1G>C
NM_001354626.2:c.-36-1G>C
NM_001354627.2:c.-36-1G>C
NM_001354628.2:c.1039-1G>C
NM_001354629.2:c.940-1G>C
NM_001354630.2:c.1039-1G>C
LRG_216t1:c.1039-1G>C
LRG_216:g.37287G>C
NC_000003.11:g.37067127G>C
NM_000249.3:c.1039-1G>C

Links:

dbSNP: rs267607819

NCBI 1000 Genomes Browser:

rs267607819

Molecular consequence:

NM_000249.4:c.1039-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167617.3:c.745-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167618.3:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001167619.3:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258271.2:c.1039-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258273.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001258274.3:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354615.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354616.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354617.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354618.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354619.2:c.316-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354620.2:c.745-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354621.2:c.16-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354622.2:c.16-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354623.2:c.16-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354624.2:c.-36-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354625.2:c.-36-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354626.2:c.-36-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354627.2:c.-36-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354628.2:c.1039-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354629.2:c.940-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354630.2:c.1039-1G>C - 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
SCV005033498	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10200055, 11306449, 9322509 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005033498

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 28, 2023)

germline

clinical testing

PubMed (3)
[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

Mutation sharing, predominant involvement of the MLH1 gene and description of four novel mutations in hereditary nonpolyposis colorectal cancer. Mutations in brief no. 144. Online.

Holmberg M, Kristo P, Chadwicks RB, Mecklin JP, Järvinen H, de la Chapelle A, Nyström-Lahti M, Peltomäki P.

Hum Mutat. 1998;11(6):482.

PubMed [citation]

PMID:: 10200055

Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.

Schweizer P, Moisio AL, Kuismanen SA, Truninger K, Vierumäki R, Salovaara R, Arola J, Butzow R, Jiricny J, Peltomäki P, Nyström-Lahti M.

Cancer Res. 2001 Apr 1;61(7):2813-5.

PubMed [citation]

PMID:: 11306449

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV005033498.1

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

Description

The c.1039-1G>C intronic pathogenic variant results from a G to C substitution one nucleotide upstream from coding exon 12 of the MLH1 gene. Other alterations impacting the same acceptor site (c.1039-1G>T and c.1039-1G>A) have been detected in individuals meeting Amsterdam I/II criteria and had Lynch syndrome-associated tumors that demonstrated loss of MLH1 on immunohistochemistry (Ambry internal data; Schweizer P et al. Cancer Res, 2001 Apr;61:2813-5; Holmberg M et al. Hum Mutat, 1998;11:482). In addition, RNA studies demonstrated MLH1 c.1039-1G>A resulted in coding exon 12 skipping (Holmberg M et al. Hum Mutat, 1998;11:482; Peltomäki P et al. Gastroenterology, 1997 Oct;113:1146-58). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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. Based on the supporting evidence, this alteration is interpreted 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: Sep 29, 2024

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