NM_000249.4(MLH1):c.194_195insAT (p.Thr66fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 21, 2017
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:: RCV001383721.2

Allele description [Variation Report for NM_000249.4(MLH1):c.194_195insAT (p.Thr66fs)]

NM_000249.4(MLH1):c.194_195insAT (p.Thr66fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.194_195insAT (p.Thr66fs)

HGVS:

NC_000003.12:g.36996696_36996697insAT
NG_007109.2:g.8347_8348insAT
NG_008418.1:g.1608_1609insAT
NM_000249.4:c.194_195insATMANE SELECT
NM_001167617.3:c.-96_-95insAT
NM_001167618.3:c.-530_-529insAT
NM_001167619.3:c.-438_-437insAT
NM_001258271.2:c.194_195insAT
NM_001258273.2:c.-517+3033_-517+3034insAT
NM_001258274.3:c.-675_-674insAT
NM_001354615.2:c.-433_-432insAT
NM_001354616.2:c.-438_-437insAT
NM_001354617.2:c.-530_-529insAT
NM_001354618.2:c.-530_-529insAT
NM_001354619.2:c.-530_-529insAT
NM_001354620.2:c.-96_-95insAT
NM_001354621.2:c.-623_-622insAT
NM_001354622.2:c.-736_-735insAT
NM_001354623.2:c.-723+2806_-723+2807insAT
NM_001354624.2:c.-633_-632insAT
NM_001354625.2:c.-536_-535insAT
NM_001354626.2:c.-633_-632insAT
NM_001354627.2:c.-633_-632insAT
NM_001354628.2:c.194_195insAT
NM_001354629.2:c.194_195insAT
NM_001354630.2:c.194_195insAT
NP_000240.1:p.Thr66fs
NP_001245200.1:p.Thr66fs
NP_001341557.1:p.Thr66fs
NP_001341558.1:p.Thr66fs
NP_001341559.1:p.Thr66fs
LRG_216:g.8347_8348insAT
NC_000003.11:g.37038187_37038188insAT

Protein change:

T66fs

Links:

dbSNP: rs2125711634

NCBI 1000 Genomes Browser:

rs2125711634

Molecular consequence:

NM_001167617.3:c.-96_-95insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-530_-529insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-438_-437insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-675_-674insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-433_-432insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-438_-437insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-530_-529insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-530_-529insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-530_-529insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-96_-95insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-623_-622insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-736_-735insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-633_-632insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-536_-535insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-633_-632insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-633_-632insAT - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.194_195insAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.194_195insAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.194_195insAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.194_195insAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.194_195insAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.-517+3033_-517+3034insAT - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2806_-723+2807insAT - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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LuxR family transcriptional regulator [Burkholderia cenocepacia]
LuxR family transcriptional regulator [Burkholderia cenocepacia]
gi|1409814745|gb|RAS58829.1||gnl|WG O|2774507552

Protein
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001582973	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 21, 2017)	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

SCV001582973

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 21, 2017)

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, SCV001582973.1

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

Description

This sequence change creates a premature translational stop signal (p.Thr66Serfs*14) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

#	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

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