NM_000249.4(MLH1):c.673_676del (p.Ser225fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 7, 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:: RCV002371907.2

Allele description [Variation Report for NM_000249.4(MLH1):c.673_676del (p.Ser225fs)]

NM_000249.4(MLH1):c.673_676del (p.Ser225fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.673_676del (p.Ser225fs)

HGVS:

NC_000003.12:g.37012095_37012098del
NG_007109.2:g.23746_23749del
NM_000249.4:c.673_676delMANE SELECT
NM_001167617.3:c.379_382del
NM_001167618.3:c.-51_-48del
NM_001167619.3:c.-51_-48del
NM_001258271.2:c.673_676del
NM_001258273.2:c.-51_-48del
NM_001258274.3:c.-51_-48del
NM_001354615.2:c.-51_-48del
NM_001354616.2:c.-51_-48del
NM_001354617.2:c.-51_-48del
NM_001354618.2:c.-51_-48del
NM_001354619.2:c.-51_-48del
NM_001354620.2:c.379_382del
NM_001354621.2:c.-144_-141del
NM_001354622.2:c.-257_-254del
NM_001354623.2:c.-257_-254del
NM_001354624.2:c.-154_-151del
NM_001354625.2:c.-154_-151del
NM_001354626.2:c.-154_-151del
NM_001354627.2:c.-154_-151del
NM_001354628.2:c.673_676del
NM_001354629.2:c.574_577del
NM_001354630.2:c.673_676del
NP_000240.1:p.Ser225fs
NP_001161089.1:p.Ser127fs
NP_001245200.1:p.Ser225fs
NP_001341549.1:p.Ser127fs
NP_001341557.1:p.Ser225fs
NP_001341558.1:p.Ser192fs
NP_001341559.1:p.Ser225fs
LRG_216:g.23746_23749del
NC_000003.11:g.37053586_37053589del
NM_000249.3:c.673_676delAGTC
NM_000249.4:c.673_676del

Protein change:

S127fs

Links:

dbSNP: rs267607774

NCBI 1000 Genomes Browser:

rs267607774

Molecular consequence:

NM_001167618.3:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-51_-48del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-144_-141del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-257_-254del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-257_-254del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-154_-151del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-154_-151del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-154_-151del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-154_-151del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.673_676del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.379_382del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.673_676del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.379_382del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.673_676del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.574_577del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.673_676del - 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
SCV002667405	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 7, 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

SCV002667405

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 7, 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

Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.

Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A.

Hum Genet. 1999 Jul-Aug;105(1-2):79-85.

PubMed [citation]

PMID:: 10480359

Details of each submission

From Ambry Genetics, SCV002667405.2

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

Description

The c.673_676delAGTC variant, located in coding exon 8 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 673 to 676, causing a translational frameshift with a predicted alternate stop codon (p.S225Efs*3). This variant has been identified in an individual with a family history of Lynch-related tumors (Wang Q et al. Hum Genet;105:79-85). 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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