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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075801.7

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:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106813	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000917661	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 14, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8872463, 26681312, 27601186, 28449805, 28874130 Citation Link,
SCV004840892	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 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

SCV000106813

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000917661

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 14, 2018)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004840892

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 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	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.

Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham JM, French AJ, Halling KC, Schwab M, Goretzki P, Thibodeau SN.

Hum Mol Genet. 1996 Sep;5(9):1245-52.

PubMed [citation]

PMID:: 8872463

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK.

Genet Med. 2016 Aug;18(8):823-32. doi: 10.1038/gim.2015.166. Epub 2015 Dec 17. Erratum in: Genet Med. 2016 May;18(5):531-2. doi: 10.1038/gim.2016.21.

PubMed [citation]

PMID:: 26681312
PMCID:: PMC4985612

See all PubMed Citations (19)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106813.3

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

Description

Coding sequence variation resulting in a stop codon

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917661.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: MLH1 c.676C>T (p.Arg226X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was 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

From All of Us Research Program, National Institutes of Health, SCV004840892.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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