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NM_000249.4(MLH1):c.677G>T (p.Arg226Leu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 22, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000524313.9

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 nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000543530Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 22, 2023) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.

Bartosova Z, Fridrichova I, Bujalkova M, Wolf B, Ilencikova D, Krizan P, Hlavcak P, Palaj J, Lukac L, Lukacova M, Böör A, Haider R, Jiricny J, Nyström-Lahti M, Marra G.

Hum Mutat. 2003 Apr;21(4):449.

PubMed [citation]
PMID:
12655568
See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543530.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 226 of the MLH1 protein (p.Arg226Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8566964, 12655568, 16830052, 17510385, 18383312, 20223024; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90319). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 8 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.677G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12547705, 15300854, 16341550, 18561205, 21034533). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2024