NM_000249.4(MLH1):c.52del (p.Arg18fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 20, 2019
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:: RCV001039846.6

Allele description [Variation Report for NM_000249.4(MLH1):c.52del (p.Arg18fs)]

NM_000249.4(MLH1):c.52del (p.Arg18fs)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.52del (p.Arg18fs)

HGVS:

NC_000003.12:g.36993599del
NG_007109.2:g.5250del
NG_008418.1:g.4707del
NM_000249.4:c.52delMANE SELECT
NM_001167617.3:c.-465del
NM_001167618.3:c.-894del
NM_001167619.3:c.-807del
NM_001258271.2:c.52del
NM_001258273.2:c.-581del
NM_001258274.3:c.-1044del
NM_001354615.2:c.-575del
NM_001354616.2:c.-575del
NM_001354617.2:c.-667del
NM_001354618.2:c.-899del
NM_001354619.2:c.-1023del
NM_001354620.2:c.-233del
NM_001354621.2:c.-992del
NM_001354622.2:c.-1105del
NM_001354623.2:c.-1014del
NM_001354624.2:c.-775del
NM_001354625.2:c.-673del
NM_001354626.2:c.-770del
NM_001354627.2:c.-1002del
NM_001354628.2:c.52del
NM_001354629.2:c.52del
NM_001354630.2:c.52del
NP_000240.1:p.Arg18fs
NP_001245200.1:p.Arg18fs
NP_001341557.1:p.Arg18fs
NP_001341558.1:p.Arg18fs
NP_001341559.1:p.Arg18fs
LRG_216:g.5250del
NC_000003.11:g.37035089del
NC_000003.11:g.37035090del
NM_000249.3:c.52delC
p.Arg18fs

Protein change:

R18fs

Links:

dbSNP: rs63749804

NCBI 1000 Genomes Browser:

rs63749804

Molecular consequence:

NM_001167617.3:c.-465del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-894del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-807del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-581del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1044del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-575del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-575del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-667del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-899del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1023del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-233del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-992del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1105del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1014del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-775del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-673del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-770del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1002del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.52del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.52del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.52del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.52del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.52del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001203395	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 20, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15713769, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001203395

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 20, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001203395.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in a family affected with colorectal cancer (PMID:¬†12132870). ClinVar contains an entry for this variant (Variation ID: 90254). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg18Alafs*18) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.

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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine