NM_000249.4(MLH1):c.1409+1G>A AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 1, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000519388.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1409+1G>A]

NM_000249.4(MLH1):c.1409+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.1409+1G>A

HGVS:

NC_000003.12:g.37026008G>A
NG_007109.2:g.37659G>A
NM_000249.4:c.1409+1G>AMANE SELECT
NM_001167617.3:c.1115+1G>A
NM_001167618.3:c.686+1G>A
NM_001167619.3:c.686+1G>A
NM_001258271.2:c.1409+1G>A
NM_001258273.2:c.686+1G>A
NM_001258274.3:c.686+1G>A
NM_001354615.2:c.686+1G>A
NM_001354616.2:c.686+1G>A
NM_001354617.2:c.686+1G>A
NM_001354618.2:c.686+1G>A
NM_001354619.2:c.686+1G>A
NM_001354620.2:c.1115+1G>A
NM_001354621.2:c.386+1G>A
NM_001354622.2:c.386+1G>A
NM_001354623.2:c.386+1G>A
NM_001354624.2:c.335+1G>A
NM_001354625.2:c.335+1G>A
NM_001354626.2:c.335+1G>A
NM_001354627.2:c.335+1G>A
NM_001354628.2:c.1409+1G>A
NM_001354629.2:c.1310+1G>A
NM_001354630.2:c.1409+1G>A
LRG_216t1:c.1409+1G>A
LRG_216:g.37659G>A
NC_000003.11:g.37067499G>A
NM_000249.3:c.1409+1G>A

Links:

dbSNP: rs267607825

NCBI 1000 Genomes Browser:

rs267607825

Molecular consequence:

NM_000249.4:c.1409+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167617.3:c.1115+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167618.3:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167619.3:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258271.2:c.1409+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258273.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001258274.3:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354615.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354616.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354617.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354618.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354619.2:c.686+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354620.2:c.1115+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354621.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354622.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354623.2:c.386+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354624.2:c.335+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354625.2:c.335+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354626.2:c.335+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354627.2:c.335+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354628.2:c.1409+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354629.2:c.1310+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354630.2:c.1409+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617551	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 20, 2017)	germline	clinical testing	Citation Link,
SCV000821733	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617551

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 20, 2017)

germline

clinical testing

Citation Link,

SCV000821733

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2020)

germline

clinical testing

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

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
not provided	germline	yes	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

Details of each submission

From GeneDx, SCV000617551.2

#	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 denoted MLH1 c.1409+1G>A or IVS12+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 12 of the MLH1 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one family withuterine and colorectal cancer (Irmejs 2007) and an alternate change, MLH1 c.1409+1G>C, has been observed in atleast one family meeting Amsterdam Criteria for Lynch syndrome (PeltomÃ¤ki 1997, Kurzawski 2002). Based on thecurrent evidence, we consider MLH1 c.1409+1G>A to be pathogenic.

#	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 GeneKor MSA, SCV000821733.2

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

Description

This variant is a substitution of the first nucleotide of intron 12 of the MLH1 gene. This position is highly conserved in human and other genomes. It is expected that this variant affects the correct mRNA splicing and results in the deletion of an entire exon. This causes the formation of a truncated non functional protein. This mutation has been described in international literature in families with suspected Lynch syndrome (PMID: 17348456).

#	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 18, 2024

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