NM_000249.4(MLH1):c.22del (p.Ile8fs) AND Hereditary nonpolyposis colorectal neoplasms

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 14, 2020
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:: RCV001382311.3

Allele description

NM_000249.4(MLH1):c.22del (p.Ile8fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.22del (p.Ile8fs)

HGVS:

NC_000003.12:g.36993569del
NG_007109.2:g.5220del
NG_008418.1:g.4736del
NM_000249.4:c.22delMANE SELECT
NM_001167617.3:c.-495del
NM_001167618.3:c.-924del
NM_001167619.3:c.-837del
NM_001258271.2:c.22del
NM_001258273.2:c.-611del
NM_001258274.3:c.-1074del
NM_001354615.2:c.-605del
NM_001354616.2:c.-605del
NM_001354617.2:c.-697del
NM_001354618.2:c.-929del
NM_001354619.2:c.-1053del
NM_001354620.2:c.-263del
NM_001354621.2:c.-1022del
NM_001354622.2:c.-1135del
NM_001354623.2:c.-1044del
NM_001354624.2:c.-805del
NM_001354625.2:c.-703del
NM_001354626.2:c.-800del
NM_001354627.2:c.-1032del
NM_001354628.2:c.22del
NM_001354629.2:c.22del
NM_001354630.2:c.22del
NP_000240.1:p.Ile8fs
NP_001245200.1:p.Ile8fs
NP_001341557.1:p.Ile8fs
NP_001341558.1:p.Ile8fs
NP_001341559.1:p.Ile8fs
LRG_216:g.5220del
NC_000003.11:g.37035060del

Protein change:

I8fs

Links:

dbSNP: rs2125693612

NCBI 1000 Genomes Browser:

rs2125693612

Molecular consequence:

NM_001167617.3:c.-495del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-924del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-837del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-611del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1074del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-605del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-605del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-697del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-929del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1053del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-263del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1022del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1135del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1044del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-805del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-703del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-800del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1032del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.22del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

Recent activity

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probable LRR receptor-like serine/threonine-protein kinase At2g16250 [Oryza sati...
probable LRR receptor-like serine/threonine-protein kinase At2g16250 [Oryza sativa Japonica Group]
gi|1002256734|ref|XP_015632675.1|

Protein
ras-related protein Ral-A [Rattus norvegicus]
ras-related protein Ral-A [Rattus norvegicus]
gi|13592039|ref|NP_112355.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580994	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 14, 2020)	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

SCV001580994

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 14, 2020)

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 Invitae, SCV001580994.3

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

Description

This variant has not been reported in the literature in individuals with MLH1-related conditions. 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 is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile8Phefs*9) 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: May 7, 2024

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