NM_000249.4(MLH1):c.677G>T (p.Arg226Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 7, 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:: RCV000160555.28

Allele description [Variation Report for NM_000249.4(MLH1):c.677G>T (p.Arg226Leu)]

NM_000249.4(MLH1):c.677G>T (p.Arg226Leu)

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.677G>T (p.Arg226Leu)

Other names:

p.R226L:CGA>CTA

HGVS:

NC_000003.12:g.37012099G>T
NG_007109.2:g.23750G>T
NM_000249.4:c.677G>TMANE SELECT
NM_001167617.3:c.383G>T
NM_001167618.3:c.-47G>T
NM_001167619.3:c.-47G>T
NM_001258271.2:c.677G>T
NM_001258273.2:c.-47G>T
NM_001258274.3:c.-47G>T
NM_001354615.2:c.-47G>T
NM_001354616.2:c.-47G>T
NM_001354617.2:c.-47G>T
NM_001354618.2:c.-47G>T
NM_001354619.2:c.-47G>T
NM_001354620.2:c.383G>T
NM_001354621.2:c.-140G>T
NM_001354622.2:c.-253G>T
NM_001354623.2:c.-253G>T
NM_001354624.2:c.-150G>T
NM_001354625.2:c.-150G>T
NM_001354626.2:c.-150G>T
NM_001354627.2:c.-150G>T
NM_001354628.2:c.677G>T
NM_001354629.2:c.578G>T
NM_001354630.2:c.677G>T
NP_000240.1:p.Arg226Leu
NP_000240.1:p.Arg226Leu
NP_001161089.1:p.Arg128Leu
NP_001245200.1:p.Arg226Leu
NP_001341549.1:p.Arg128Leu
NP_001341557.1:p.Arg226Leu
NP_001341558.1:p.Arg193Leu
NP_001341559.1:p.Arg226Leu
LRG_216t1:c.677G>T
LRG_216:g.23750G>T
LRG_216p1:p.Arg226Leu
NC_000003.11:g.37053590G>T
NM_000249.3:c.677G>T
P40692:p.Arg226Leu

Protein change:

R128L

Links:

UniProtKB: P40692#VAR_004451; dbSNP: rs63751711

NCBI 1000 Genomes Browser:

rs63751711

Molecular consequence:

NM_001167618.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-140G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-253G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-253G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.578G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211133	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Nov 19, 2018)	germline	clinical testing	Citation Link,
SCV000592367	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001248017	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2017)	germline	clinical testing	Citation Link,
SCV002047319	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Feb 16, 2021)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 8566964, 20223024, 16830052, 12655568, 29505604, 18561205, 18772310, 17510385, 18383312, 26467025
SCV005199141	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 7, 2023)	germline	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.

Maliaka YK, Chudina AP, Belev NF, Alday P, Bochkov NP, Buerstedde JM.

Hum Genet. 1996 Feb;97(2):251-5.

PubMed [citation]

PMID:: 8566964

Some aspects of molecular diagnostics in Lynch syndrome.

Kurzawski G.

Hered Cancer Clin Pract. 2006 Dec 15;4(4):197-205. doi: 10.1186/1897-4287-4-4-197.

PubMed [citation]

PMID:: 20223024
PMCID:: PMC2837309

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000211133.12

#	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 denoted MLH1 c.677G>T at the cDNA level. Located in the last nucleotide of exon 8, it destroys a natural splice site and causes abnormal splicing. Multiple studies report, but do not quantify, aberrant splicing caused by this variant that results in skipping of exon 8 (Maliaka 1996, Kurzawski 2006, Hardt 2011). This is concordant with multiple protein and RNA analyses of an alternate variant at this position, MLH1 c.677G>A, which have consistently demonstrated that it causes complete skipping of exon 8 (Leung 1998, Sharp 2004, Pagenstecher 2006, Tournier 2008). In addition, in vitro functional assays of MLH1 c.677G>T showed reduced mismatch repair activity and possibly reduced protein expression (Takahashi 2007). MLH1 c.677G>T has been observed in multiple individuals with early-onset colorectal, endometrial, or gastric cancer whose family histories fulfilled Bethesda or Amsterdam Criteria for Hereditary Nonpolyposis Colorectal Cancer, but also in a sporadic gastric tumor (Maliaka 1996, Evans 2001, Kurzawski 2002, Bartosova 2003, Wagner 2003, Kurzawski 2006, Zavodna 2006, Alemayehu 2008, Hardt 2011, Schofield 2012, Raskin 2017, Martin-Morales 2018). Tumor testing in many of these individuals showed microsatellite instability and loss of MLH1 protein expression, and Bujalkova et al. (2008) found tumoral loss of heterozygosity. In addition, MLH1 c. 677G>T co-occurred with two other pathogenic variants, one in BRCA2 and one in MSH6, in an individual with early-onset endometrial cancer and bilinear family history (Gong 2012). Although the nucleotide substitution results in the change of an Arginine to a Leucine at codon 226, and is called Arg226Leu in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. MLH1 c.677G>T was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 677, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592367.2

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

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

From CeGaT Center for Human Genetics Tuebingen, SCV001248017.26

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

#	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		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047319.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This variant has been reported in individuals affected with Lynch syndrome or related cancers in the published literature (PMID: 18772310 (2008), 20223024 (2006), 16830052 (2006), 12655568 (2003), 8566964 (1996)). Additionally, functional studies have determined that this variant interferes with normal MLH1 mRNA splicing and is damaging to the mismatch repair (MMR) activity of the MLH1 protein (PMID: 29505604 (2018), 18561205 (2008), 17510385 (2007)). Based on the available information, the variant is classified as pathogenic.

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199141.1

#	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

Last Updated: Oct 20, 2024

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