NM_000249.4(MLH1):c.2174_2181del (p.Arg725fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 2, 2021
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:: RCV002432775.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2174_2181del (p.Arg725fs)]

NM_000249.4(MLH1):c.2174_2181del (p.Arg725fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2174_2181del (p.Arg725fs)

HGVS:

NC_000003.12:g.37050556_37050563del
NG_007109.2:g.62207_62214del
NM_000249.4:c.2174_2181delMANE SELECT
NM_001167617.3:c.1880_1887del
NM_001167618.3:c.1451_1458del
NM_001167619.3:c.1451_1458del
NM_001258271.2:c.1967_1974del
NM_001258273.2:c.1451_1458del
NM_001258274.3:c.1451_1458del
NM_001354615.2:c.1451_1458del
NM_001354616.2:c.1451_1458del
NM_001354617.2:c.1451_1458del
NM_001354618.2:c.1451_1458del
NM_001354619.2:c.1451_1458del
NM_001354620.2:c.1880_1887del
NM_001354621.2:c.1151_1158del
NM_001354622.2:c.1151_1158del
NM_001354623.2:c.1151_1158del
NM_001354624.2:c.1100_1107del
NM_001354625.2:c.1100_1107del
NM_001354626.2:c.1100_1107del
NM_001354627.2:c.1100_1107del
NM_001354628.2:c.2081_2088del
NM_001354629.2:c.2075_2082del
NM_001354630.2:c.2009_2016del
NP_000240.1:p.Arg725Hisfs
NP_000240.1:p.Arg725fs
NP_001161089.1:p.Arg627fs
NP_001161090.1:p.Arg484fs
NP_001161091.1:p.Arg484fs
NP_001245200.1:p.Arg656fs
NP_001245202.1:p.Arg484fs
NP_001245203.1:p.Arg484fs
NP_001341544.1:p.Arg484fs
NP_001341545.1:p.Arg484fs
NP_001341546.1:p.Arg484fs
NP_001341547.1:p.Arg484fs
NP_001341548.1:p.Arg484fs
NP_001341549.1:p.Arg627fs
NP_001341550.1:p.Arg384fs
NP_001341551.1:p.Arg384fs
NP_001341552.1:p.Arg384fs
NP_001341553.1:p.Arg367fs
NP_001341554.1:p.Arg367fs
NP_001341555.1:p.Arg367fs
NP_001341556.1:p.Arg367fs
NP_001341557.1:p.Arg694fs
NP_001341558.1:p.Arg692fs
NP_001341559.1:p.Arg670fs
LRG_216t1:c.2174_2181del
LRG_216:g.62207_62214del
LRG_216p1:p.Arg725Hisfs
NC_000003.11:g.37092047_37092054del
NM_000249.3:c.2174_2181delGCTCACAC

Protein change:

R367fs

Molecular consequence:

NM_000249.4:c.2174_2181del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1880_1887del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1967_1974del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1451_1458del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1880_1887del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1151_1158del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1151_1158del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1151_1158del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1100_1107del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1100_1107del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1100_1107del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1100_1107del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2081_2088del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2075_2082del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2009_2016del - 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

Recent activity

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alpha/beta fold hydrolase [Luteibacter sp.]
alpha/beta fold hydrolase [Luteibacter sp.]
gi|2674045002|ref|WP_331645372.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002726673	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 2, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002726673

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 2, 2021)

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, SCV002726673.2

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

Description

The c.2174_2181delGCTCACAC pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of 8 nucleotides at nucleotide positions 2174 to 2181, causing a translational frameshift with a predicted alternate stop codon (p.R725Hfs*5). This alteration occurs at the 3' terminus of the MLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 32 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, 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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