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NM_000249.4(MLH1):c.677G>T (p.Arg226Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Mar 29, 2022
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:
RCV000708610.9

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]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000821736GeneKor MSA
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 1, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001187870Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Mar 29, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002528769Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Pathogenic
(Oct 20, 2020)
germlinecuration

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004359196Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 22, 2021)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]
PMID:
16451135

Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort.

Raskin L, Guo Y, Du L, Clendenning M, Rosty C; Colon Cancer Family Registry (CCFR)., Lindor NM, Gruber SB, Buchanan DD.

Oncotarget. 2017 Nov 7;8(55):93450-93463. doi: 10.18632/oncotarget.18596.

PubMed [citation]
PMID:
29212164
PMCID:
PMC5706810
See all PubMed Citations (14)

Details of each submission

From GeneKor MSA, SCV000821736.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variation is a single nucleotide substitution, resulting in the replacement of Arginine with Leucine at codon 226 of the MLH1 protein. The arginine residue is conserved among species and is located in a functional domain of the protein. There is a large physiochemical difference between leucine and leucine (Grantham Score 102).This variant has been reported in the literature in in multiple individuals affected with Lynch syndrome (PMID: 18383312, PMID: 20223024, PMID: 16830052, PMID: 12655568). Loss of MLH1 protein and microsatellite instability has been detected in many of these cases in the tumor tissue (PMID: 18772310). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. In vitro functional assays showed reduced mismatch repair activity and possibly reduced protein expression (PMID: 17510385 ).The mutation databases (ClinVar, InSiGHT) contain entries for this variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV001187870.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The c.677G>T pathogenic mutation (also known as p.R226L), located in coding exon 8 of the MLH1 gene, results from a G to T substitution at nucleotide position 677. This change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple families meeting either Amsterdam diagnostic criteria or Bethesda guidelines for Lynch syndrome (Maliaka YK et al. Hum. Genet., 1996 Feb;97:251-5; Kurzawski G et al. Clin. Genet., 2006 Jan;69:40-7; Alemayehu A et al. Genes Chromosomes Cancer. 2008 Oct;47(10):906-14; Wagner A et al. Am J Hum Genet. 2003 May;72(5):1088-100; Bartosova Z et al. Hum. Mutat. 2003 Apr;21(4):449; Zavodna K et al. Neoplasma 2006 ;53(4):269-76; Evans DG et al. J. Natl. Cancer Inst. 2001 May;93(9):716-7). Functional RNA studies have demonstrated abnormal splicing for this variant with out-of-frame exon 8 skipping (Ambry internal data; Kurzawski G et al. Clin. Genet., 2006 Jan;69:40-7). In addition, in an in vitro complementation assay, the p.R226L variant showed decreased MMR activity (Takahashi et al. Cancer Res. 2007. 67(10):4595-4604). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Sema4, Sema4, SCV002528769.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV004359196.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This missense variant replaces arginine with leucine at codon 226 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional RNA studies or assays of patient RNA or cDNA have shown that this variant causes exon 8 deletion predicted to result in a premature truncation (PMID: 15300854,16341550, 18561205, 29505604). The variant protein in HCT116 cells was reported to have 32% of wild-type DNA mismatch repair (PMID: 17510385). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8566964, 15300854, 16341550 16830052, 20223024, 21034533, 30256826). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024