U.S. flag

An official website of the United States government

NM_000249.4(MLH1):c.676C>T (p.Arg226Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 31, 2024
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:
RCV000524311.8

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]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000284071Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 31, 2024) 		germlineclinical testing

PubMed (11)
[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

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]
PMID:
15713769
PMCID:
PMC2933041

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]
PMID:
24362816
PMCID:
PMC4294709
See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284071.8

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

Description

This sequence change creates a premature translational stop signal (p.Arg226*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is present in population databases (rs63751615, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 8872463, 10874307, 15655560, 15849733, 17889038, 21247423, 23047549, 24344984). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17087). 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 20, 2024