NM_000249.4(MLH1):c.2149del (p.Glu717fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 14, 2018
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:: RCV002432413.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2149del (p.Glu717fs)]

NM_000249.4(MLH1):c.2149del (p.Glu717fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2149del (p.Glu717fs)

HGVS:

NC_000003.12:g.37050531del
NG_007109.2:g.62182del
NM_000249.4:c.2149delMANE SELECT
NM_001167617.3:c.1855del
NM_001167618.3:c.1426del
NM_001167619.3:c.1426del
NM_001258271.2:c.1942del
NM_001258273.2:c.1426del
NM_001258274.3:c.1426del
NM_001354615.2:c.1426del
NM_001354616.2:c.1426del
NM_001354617.2:c.1426del
NM_001354618.2:c.1426del
NM_001354619.2:c.1426del
NM_001354620.2:c.1855del
NM_001354621.2:c.1126del
NM_001354622.2:c.1126del
NM_001354623.2:c.1126del
NM_001354624.2:c.1075del
NM_001354625.2:c.1075del
NM_001354626.2:c.1075del
NM_001354627.2:c.1075del
NM_001354628.2:c.2056del
NM_001354629.2:c.2050del
NM_001354630.2:c.1984del
NP_000240.1:p.Glu717Asnfs
NP_000240.1:p.Glu717fs
NP_001161089.1:p.Glu619fs
NP_001161090.1:p.Glu476fs
NP_001161091.1:p.Glu476fs
NP_001245200.1:p.Glu648fs
NP_001245202.1:p.Glu476fs
NP_001245203.1:p.Glu476fs
NP_001341544.1:p.Glu476fs
NP_001341545.1:p.Glu476fs
NP_001341546.1:p.Glu476fs
NP_001341547.1:p.Glu476fs
NP_001341548.1:p.Glu476fs
NP_001341549.1:p.Glu619fs
NP_001341550.1:p.Glu376fs
NP_001341551.1:p.Glu376fs
NP_001341552.1:p.Glu376fs
NP_001341553.1:p.Glu359fs
NP_001341554.1:p.Glu359fs
NP_001341555.1:p.Glu359fs
NP_001341556.1:p.Glu359fs
NP_001341557.1:p.Glu686fs
NP_001341558.1:p.Glu684fs
NP_001341559.1:p.Glu662fs
LRG_216t1:c.2149del
LRG_216:g.62182del
LRG_216p1:p.Glu717Asnfs
NC_000003.11:g.37092022del
NM_000249.3:c.2149delG

Protein change:

E359fs

Molecular consequence:

NM_000249.4:c.2149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1855del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1942del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1426del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1855del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1126del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1126del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1126del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1075del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1075del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1075del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1075del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2056del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2050del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.1984del - 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
SCV002728014	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 14, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002728014

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 14, 2018)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV002728014.2

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

Description

The c.2149delG variant, located in coding exon 19 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 2149, causing a translational frameshift with a predicted alternate stop codon (p.E717Nfs*66). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 25 amino acids. This alteration is predicted to perturb a known functional domain responsible for binding to PMS2 and remove a cysteine shown to be involved in metal binding as part of a functional domain in PMS2 (Ambry Internal Data). Based on the majority of available evidence to date, 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: May 1, 2024

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