U.S. flag

An official website of the United States government

NM_000249.4(MLH1):c.793C>T (p.Arg265Cys) AND Carcinoma of colon

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 10, 2018
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:
RCV000677879.9

Allele description [Variation Report for NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)]

NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)

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.793C>T (p.Arg265Cys)
HGVS:
  • NC_000003.12:g.37017508C>T
  • NG_007109.2:g.29159C>T
  • NM_000249.4:c.793C>TMANE SELECT
  • NM_001167617.3:c.499C>T
  • NM_001167618.3:c.70C>T
  • NM_001167619.3:c.70C>T
  • NM_001258271.2:c.793C>T
  • NM_001258273.2:c.70C>T
  • NM_001258274.3:c.70C>T
  • NM_001354615.2:c.70C>T
  • NM_001354616.2:c.70C>T
  • NM_001354617.2:c.70C>T
  • NM_001354618.2:c.70C>T
  • NM_001354619.2:c.70C>T
  • NM_001354620.2:c.499C>T
  • NM_001354621.2:c.-139-2802C>T
  • NM_001354622.2:c.-139-2802C>T
  • NM_001354623.2:c.-139-2802C>T
  • NM_001354624.2:c.-37+2964C>T
  • NM_001354625.2:c.-37+2964C>T
  • NM_001354626.2:c.-37+2964C>T
  • NM_001354627.2:c.-37+2964C>T
  • NM_001354628.2:c.793C>T
  • NM_001354629.2:c.694C>T
  • NM_001354630.2:c.793C>T
  • NP_000240.1:p.Arg265Cys
  • NP_000240.1:p.Arg265Cys
  • NP_001161089.1:p.Arg167Cys
  • NP_001161090.1:p.Arg24Cys
  • NP_001161091.1:p.Arg24Cys
  • NP_001245200.1:p.Arg265Cys
  • NP_001245202.1:p.Arg24Cys
  • NP_001245203.1:p.Arg24Cys
  • NP_001341544.1:p.Arg24Cys
  • NP_001341545.1:p.Arg24Cys
  • NP_001341546.1:p.Arg24Cys
  • NP_001341547.1:p.Arg24Cys
  • NP_001341548.1:p.Arg24Cys
  • NP_001341549.1:p.Arg167Cys
  • NP_001341557.1:p.Arg265Cys
  • NP_001341558.1:p.Arg232Cys
  • NP_001341559.1:p.Arg265Cys
  • LRG_216t1:c.793C>T
  • LRG_216:g.29159C>T
  • LRG_216p1:p.Arg265Cys
  • NC_000003.11:g.37058999C>T
  • NM_000249.3:c.793C>T
  • NM_001167618.1:c.70C>T
  • P40692:p.Arg265Cys
  • uc010hgn.1:c.793C>T
Protein change:
R167C; ARG265CYS
Links:
UniProtKB: P40692#VAR_054530; OMIM: 120436.0030; dbSNP: rs63751194
NCBI 1000 Genomes Browser:
rs63751194
Molecular consequence:
  • NM_001354621.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-139-2802C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-37+2964C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.70C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
9

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000592378Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

SCV0008040403DMed Clinical Laboratory Inc
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 10, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes9not providednot providednot providednot providedclinical testing

Citations

PubMed

Functional characterization of MLH1 missense variants identified in Lynch syndrome patients.

Andersen SD, Liberti SE, Lützen A, Drost M, Bernstein I, Nilbert M, Dominguez M, Nyström M, Hansen TV, Christoffersen JW, Jäger AC, de Wind N, Nielsen FC, Tørring PM, Rasmussen LJ.

Hum Mutat. 2012 Dec;33(12):1647-55. doi: 10.1002/humu.22153. Epub 2012 Jul 23.

PubMed [citation]
PMID:
22753075

The MLH1 variants p.Arg265Cys and p.Lys618Ala affect protein stability while p.Leu749Gln affects heterodimer formation.

Perera S, Bapat B.

Hum Mutat. 2008 Feb;29(2):332. doi: 10.1002/humu.9523.

PubMed [citation]
PMID:
18205192
See all PubMed Citations (4)

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592378.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not providednot providedclinical testingnot provided

Description

The p.Arg265Cys variant has been previously reported in the literature and by our laboratory. It is also reported in dbSNP from a clinical source (dbSNP#:rs63751194). In one study, this variant was reported in 2 different families and was associated with skipping of exons 9 and 10 from cDNA (Casey 2005). In another report, including probands who met Amsterdam criteria for HNPCC or who had a family history, this variant was found to reduce exon inclusion. This variant has been tested in different functional assays at the protein level, with results that were not always consistent; the p.Arg265Cys was associated with a mild reduction of mismatch repair efficiency in four studies (Plotz 2006; Ellison 2001; Wanat 2007; Takahashi 2007) but not in a fifth one (Trojan 2002) (Tournier 2007). One large study of Tawainese patients demonstrated that the p.Arg265Cys variant was identified in 13 out of 93 unrelated families. In total, 93 cancers were noted in these 13 families including 66 with cases of colon cancer, 6 cases of rectal cancer, 3 cases of endometrial cancer, 6 cases of gastric cancer, 1 case of ovarian cancer and 11 cases of other types of cancer (Tang 2009). In another report, deficient MLH1 IHC status and MSI-H tumor was noted in an individual with this variant who developed colorectal cancer at age 55 (Perera 2010). In summary, based on the above information this variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided9not providednot providednot provided

From 3DMed Clinical Laboratory Inc, SCV000804040.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024