NM_000249.4(MLH1):c.31del (p.Leu11fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 14, 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:: RCV002321563.2

Allele description [Variation Report for NM_000249.4(MLH1):c.31del (p.Leu11fs)]

NM_000249.4(MLH1):c.31del (p.Leu11fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.31del (p.Leu11fs)

HGVS:

NC_000003.12:g.36993578del
NG_007109.2:g.5229del
NG_008418.1:g.4727del
NM_000249.4:c.31delMANE SELECT
NM_001167617.3:c.-486del
NM_001167618.3:c.-915del
NM_001167619.3:c.-828del
NM_001258271.2:c.31del
NM_001258273.2:c.-602del
NM_001258274.3:c.-1065del
NM_001354615.2:c.-596del
NM_001354616.2:c.-596del
NM_001354617.2:c.-688del
NM_001354618.2:c.-920del
NM_001354619.2:c.-1044del
NM_001354620.2:c.-254del
NM_001354621.2:c.-1013del
NM_001354622.2:c.-1126del
NM_001354623.2:c.-1035del
NM_001354624.2:c.-796del
NM_001354625.2:c.-694del
NM_001354626.2:c.-791del
NM_001354627.2:c.-1023del
NM_001354628.2:c.31del
NM_001354629.2:c.31del
NM_001354630.2:c.31del
NP_000240.1:p.Leu11fs
NP_001245200.1:p.Leu11fs
NP_001341557.1:p.Leu11fs
NP_001341558.1:p.Leu11fs
NP_001341559.1:p.Leu11fs
LRG_216:g.5229del
NC_000003.11:g.37035069del
NM_000249.3:c.31delC

Protein change:

L11fs

Links:

dbSNP: rs63749816

NCBI 1000 Genomes Browser:

rs63749816

Molecular consequence:

NM_001167617.3:c.-486del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-915del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-828del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-602del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1065del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-596del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-596del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-688del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-920del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1044del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-254del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1013del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1126del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1035del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-796del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-694del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-791del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1023del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.31del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.31del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.31del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.31del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.31del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002609139	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002609139

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 14, 2022)

germline

clinical testing

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

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

Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family.

Kadiyska TK, Kaneva RP, Nedin DG, Alexandrova AB, Gegova AT, Lalchev SG, Christova T, Mitev VI, Horst J, Bogdanova N, Kremensky IM.

World J Gastroenterol. 2006 Dec 28;12(48):7848-51.

PubMed [citation]

PMID:: 17203532
PMCID:: PMC4087554

Details of each submission

From Ambry Genetics, SCV002609139.2

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

Description

The c.31delC pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 31, causing a translational frameshift with a predicted alternate stop codon (p.L11Wfs*6). This variant was reported to segregate with disease in a large Bulgarian family that met Amsterdam criteria for Lynch syndrome and several family members had colon tumors that demonstrated microsatellite instability with loss of MLH1 expression on immunohistochemistry (IHC) (Kadiyska TK et al. World J Gastroenterol, 2006 Dec;12:7848-51). This variant has also been identified in a proband who met Amsterdam criteria for Lynch syndrome and tumor demonstrated loss of both MLH1/PMS2 expression on IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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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