NM_000249.4(MLH1):c.676C>T (p.Arg226Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000115485.13

Allele description [Variation Report for NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)]

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)

Other names:

p.R226*:CGA>TGA

HGVS:

NC_000003.12:g.37012098C>T
NG_007109.2:g.23749C>T
NM_000249.4:c.676C>TMANE SELECT
NM_001167617.3:c.382C>T
NM_001167618.3:c.-48C>T
NM_001167619.3:c.-48C>T
NM_001258271.2:c.676C>T
NM_001258273.2:c.-48C>T
NM_001258274.3:c.-48C>T
NM_001354615.2:c.-48C>T
NM_001354616.2:c.-48C>T
NM_001354617.2:c.-48C>T
NM_001354618.2:c.-48C>T
NM_001354619.2:c.-48C>T
NM_001354620.2:c.382C>T
NM_001354621.2:c.-141C>T
NM_001354622.2:c.-254C>T
NM_001354623.2:c.-254C>T
NM_001354624.2:c.-151C>T
NM_001354625.2:c.-151C>T
NM_001354626.2:c.-151C>T
NM_001354627.2:c.-151C>T
NM_001354628.2:c.676C>T
NM_001354629.2:c.577C>T
NM_001354630.2:c.676C>T
NP_000240.1:p.Arg226Ter
NP_000240.1:p.Arg226Ter
NP_001161089.1:p.Arg128Ter
NP_001245200.1:p.Arg226Ter
NP_001341549.1:p.Arg128Ter
NP_001341557.1:p.Arg226Ter
NP_001341558.1:p.Arg193Ter
NP_001341559.1:p.Arg226Ter
LRG_216t1:c.676C>T
LRG_216:g.23749C>T
LRG_216p1:p.Arg226Ter
NC_000003.11:g.37053589C>T
NM_000249.3:c.676C>T
NM_001167617.1:c.382C>T
p.Arg226*
p.Arg226Stop
p.R226*

Protein change:

R128*; ARG226TER

Links:

OMIM: 120436.0010; dbSNP: rs63751615

NCBI 1000 Genomes Browser:

rs63751615

Molecular consequence:

NM_001167618.3:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-48C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-141C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-254C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-254C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-151C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-151C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-151C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-151C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.676C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.382C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.676C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.382C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.676C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.577C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.676C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000212825	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 11, 2021)	germline	clinical testing	PubMed (25) [See all records that cite these PMIDs] 15655560, 16769400, 19690142, 19731080, 20045164, 20052760, 20924129, 21056691, 21247423, 21868491, 23047549, 24456667, 27601186, 27606285, 28445943, 28449805, 28514183, 28874130, 28944238, 30262796, 30521064, 31118792, 32635641, 8872463, 9927033 Citation Link,
SCV000689906	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9927033, 15655560, 15849733, 17889038, 18307539, 19690142, 20045164, 20924129, 21247423, 23047549, 24344984, 24362816, 27601186, 28514183, 28874130, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212825

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 11, 2021)

germline

clinical testing

PubMed (25)
[See all records that cite these PMIDs]

Citation Link,

SCV000689906

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

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

Mutations in the DNA mismatch repair gene MLH1 associated with early-onset colon cancer.

Marcos I, Borrego S, Urioste M, García-Vallés C, Antiñolo G.

J Pediatr. 2006 Jun;148(6):837-9.

PubMed [citation]

PMID:: 16769400

Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis.

Jasperson KW, Vu TM, Schwab AL, Neklason DW, Rodriguez-Bigas MA, Burt RW, Weitzel JN.

Fam Cancer. 2010 Jun;9(2):99-107. doi: 10.1007/s10689-009-9290-4. Erratum in: Fam Cancer. 2013 Sep;12(3):583.

PubMed [citation]

PMID:: 19731080
PMCID:: PMC3620042

See all PubMed Citations (31)

Details of each submission

From Ambry Genetics, SCV000212825.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (25)

Description

The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 676. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been detected in multiple families meeting Amsterdam Criteria for a clinical diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome), several with tumors demonstrating microsatellite instability and loss of MLH1 protein on immunohistochemistry (Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52; Marcos I et al. J Pediatr, 2006 Jun;148:837-9; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Chang SC et al. Surgery, 2010 May;147:720-8; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Giráldez MD et al. Clin Cancer Res, 2010 Nov;16:5402-13; Limburg PJ et al. Clin Gastroenterol Hepatol, 2011 Jun;9:497-502; Castillejo A et al. BMC Med. Genet., 2011;12:12; Pal T et al. Br J Cancer, 2012 Nov;107:1783-90; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72; Hinrichsen I et al. Mol Cancer, 2014 Jan;13:11; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Dámaso E et al. Cancers (Basel), 2020 Jul;12:). This mutation has been reported as homozygous in individuals with features of constitutional mismatch repair deficiency (CMMRD) syndrome (Ricciardone MD et al. Cancer Res, 1999 Jan;59:290-3; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404). This mutation has also been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:). 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

From Color Diagnostics, LLC DBA Color Health, SCV000689906.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

#	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: Oct 20, 2024

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