NM_000249.4(MLH1):c.34_46del (p.Leu11_Asp12insTer) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 31, 2019
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:: RCV001258070.1

Allele description [Variation Report for NM_000249.4(MLH1):c.34_46del (p.Leu11_Asp12insTer)]

NM_000249.4(MLH1):c.34_46del (p.Leu11_Asp12insTer)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.34_46del (p.Leu11_Asp12insTer)

HGVS:

NC_000003.12:g.36993581_36993593del
NG_007109.2:g.5232_5244del
NG_008418.1:g.4713_4725del
NM_000249.3:c.34_46del13
NM_000249.4:c.34_46delMANE SELECT
NM_001167617.3:c.-483_-471del
NM_001167618.3:c.-912_-900del
NM_001167619.3:c.-825_-813del
NM_001258271.2:c.34_46del
NM_001258273.2:c.-599_-587del
NM_001258274.3:c.-1062_-1050del
NM_001354615.2:c.-593_-581del
NM_001354616.2:c.-593_-581del
NM_001354617.2:c.-685_-673del
NM_001354618.2:c.-917_-905del
NM_001354619.2:c.-1041_-1029del
NM_001354620.2:c.-251_-239del
NM_001354621.2:c.-1010_-998del
NM_001354622.2:c.-1123_-1111del
NM_001354623.2:c.-1032_-1020del
NM_001354624.2:c.-793_-781del
NM_001354625.2:c.-691_-679del
NM_001354626.2:c.-788_-776del
NM_001354627.2:c.-1020_-1008del
NM_001354628.2:c.34_46del
NM_001354629.2:c.34_46del
NM_001354630.2:c.34_46del
NP_000240.1:p.Leu11_Asp12insTer
NP_001245200.1:p.Leu11_Asp12insTer
NP_001341557.1:p.Leu11_Asp12insTer
NP_001341558.1:p.Leu11_Asp12insTer
NP_001341559.1:p.Leu11_Asp12insTer
LRG_216t1:c.34_46del
LRG_216:g.5232_5244del
NC_000003.11:g.37035072_37035084del
NM_000249.3:c.34_46del13
NM_000249.3:c.34_46delGACGAGACAGTGG

Links:

dbSNP: rs2080891193

NCBI 1000 Genomes Browser:

rs2080891193

Molecular consequence:

NM_001167617.3:c.-483_-471del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-912_-900del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-825_-813del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-599_-587del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1062_-1050del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-593_-581del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-593_-581del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-685_-673del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-917_-905del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1041_-1029del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-251_-239del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1010_-998del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1123_-1111del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1032_-1020del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-793_-781del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-691_-679del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-788_-776del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1020_-1008del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.34_46del - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.34_46del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.34_46del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.34_46del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.34_46del - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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kelch-like protein 25 [Homo sapiens]
kelch-like protein 25 [Homo sapiens]
gi|21362105|ref|NP_071925.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001434903	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 31, 2019)	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

SCV001434903

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 31, 2019)

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

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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434903.1

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

Description

This sequence change deletes 13 nucleotides from exon 1 of the MLH1 mRNA (c.34_46delGACGAGACAGTGG) causing a premature translational stop signal at codon 12 (p.Asp12Ter). It is expected to result in protein truncation or an absent protein product via nonsense mediated decay. This variant is not present in population databases (gnomAD). While this particular deletion has not been previously reported, other loss-of-function variants in the MLH1 gene are associated with Lynch syndrome (PMID: 14635101, 15942939). Therefore, this variant has been classified as likely 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: May 1, 2024

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