NM_000249.4(MLH1):c.114del (p.Cys39fs) AND Hereditary cancer-predisposing syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 20, 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:: RCV002452530.1

Allele description

NM_000249.4(MLH1):c.114del (p.Cys39fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.114del (p.Cys39fs)

HGVS:

NC_000003.12:g.36993661del
NG_007109.2:g.5312del
NG_008418.1:g.4644del
NG_099042.1:g.54del
NM_000249.4:c.114delMANE SELECT
NM_001167617.3:c.-403del
NM_001167618.3:c.-832del
NM_001167619.3:c.-745del
NM_001258271.2:c.114del
NM_001258273.2:c.-519del
NM_001258274.3:c.-982del
NM_001354615.2:c.-513del
NM_001354616.2:c.-513del
NM_001354617.2:c.-605del
NM_001354618.2:c.-837del
NM_001354619.2:c.-961del
NM_001354620.2:c.-171del
NM_001354621.2:c.-930del
NM_001354622.2:c.-1043del
NM_001354623.2:c.-952del
NM_001354624.2:c.-713del
NM_001354625.2:c.-611del
NM_001354626.2:c.-708del
NM_001354627.2:c.-940del
NM_001354628.2:c.114del
NM_001354629.2:c.114del
NM_001354630.2:c.114del
NP_000240.1:p.Cys39Valfs
NP_000240.1:p.Cys39fs
NP_001245200.1:p.Cys39fs
NP_001341557.1:p.Cys39fs
NP_001341558.1:p.Cys39fs
NP_001341559.1:p.Cys39fs
LRG_216t1:c.114del
LRG_216:g.5312del
LRG_216p1:p.Cys39Valfs
NC_000003.11:g.37035152del
NM_000249.3:c.114delC

Protein change:

C39fs

Molecular consequence:

NM_001167617.3:c.-403del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-832del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-745del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-519del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-982del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-513del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-513del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-605del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-837del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-961del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-171del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-930del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1043del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-952del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-713del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-611del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-708del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-940del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.114del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.114del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.114del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.114del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.114del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV002613988	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Oct 20, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002613988

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Oct 20, 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	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV002613988.1

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

Description

The c.114delC pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 114, causing a translational frameshift with a predicted alternate stop codon (p.C39Vfs*2). This alteration has been identified as somatic in conjunction with MLH1 copy neutral loss of heterozygosity (CN-LOH) in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). 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	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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