NM_000249.4(MLH1):c.676C>T (p.Arg226Ter) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 27, 2024
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:: RCV000018616.35

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]

Observations:

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038899	OMIM	no assertion criteria provided	Pathogenic (May 1, 2001)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9927033, 11343035
SCV000785381	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Jul 19, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23047549, 8872463, 27601186, 9927033 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV002580789	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761605	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004018205	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Mar 16, 2023)	unknown	clinical testing	Citation Link,
SCV004193071	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer.

Huang SC, Lavine JE, Boland PS, Newbury RO, Kolodner R, Pham TT, Arnold CN, Boland CR, Carethers JM.

J Pediatr. 2001 May;138(5):629-35.

PubMed [citation]

PMID:: 11343035

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23047549
PMCID:: PMC3493867

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000038899.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic malignancy at a very early age, 2 of whom displayed signs of type I neurofibromatosis (NF1; 162200). Sequence analysis in the 3 sibs demonstrated homozygosity for a 676C-T mutation in the MLH1 gene, leading to an arg226-to-ter mutation (R226X). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents were heterozygous for the mutation and had colon cancer at an early age. The phenotype in the sibs was consistent with the mismatch repair cancer syndrome (MMRCS1; 276300), which manifests features of NF1 and hematologic malignancies.

Huang et al. (2001) studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that she was heterozygous for the R226X mutation. As this mutation is 2 bp from the 3-prime end of exon 8 and might affect donor splicing, an in vitro transcription translation assay was performed and confirmed the presence of the truncated peptide, which lacked the critical PMS2-binding regions at its C terminus.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000785381.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580789.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002761605.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004018205.1

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004193071.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine