NM_000249.4(MLH1):c.52_59del (p.Arg18fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 26, 2021
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:: RCV001961904.4

Allele description [Variation Report for NM_000249.4(MLH1):c.52_59del (p.Arg18fs)]

NM_000249.4(MLH1):c.52_59del (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.52_59del (p.Arg18fs)

HGVS:

NC_000003.12:g.36993599_36993606del
NG_007109.2:g.5250_5257del
NG_008418.1:g.4700_4707del
NM_000249.4:c.52_59delMANE SELECT
NM_001167617.3:c.-465_-458del
NM_001167618.3:c.-894_-887del
NM_001167619.3:c.-807_-800del
NM_001258271.2:c.52_59del
NM_001258273.2:c.-581_-574del
NM_001258274.3:c.-1044_-1037del
NM_001354615.2:c.-575_-568del
NM_001354616.2:c.-575_-568del
NM_001354617.2:c.-667_-660del
NM_001354618.2:c.-899_-892del
NM_001354619.2:c.-1023_-1016del
NM_001354620.2:c.-233_-226del
NM_001354621.2:c.-992_-985del
NM_001354622.2:c.-1105_-1098del
NM_001354623.2:c.-1014_-1007del
NM_001354624.2:c.-775_-768del
NM_001354625.2:c.-673_-666del
NM_001354626.2:c.-770_-763del
NM_001354627.2:c.-1002_-995del
NM_001354628.2:c.52_59del
NM_001354629.2:c.52_59del
NM_001354630.2:c.52_59del
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.5250_5257del
NC_000003.11:g.37035089_37035096del
NC_000003.11:g.37035090_37035097del

Protein change:

R18fs

Links:

dbSNP: rs2125694037

NCBI 1000 Genomes Browser:

rs2125694037

Molecular consequence:

NM_001167617.3:c.-465_-458del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-894_-887del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-807_-800del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-581_-574del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1044_-1037del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-575_-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-575_-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-667_-660del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-899_-892del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1023_-1016del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-233_-226del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-992_-985del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1105_-1098del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1014_-1007del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-775_-768del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-673_-666del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-770_-763del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1002_-995del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.52_59del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.52_59del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.52_59del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.52_59del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.52_59del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002130364	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 26, 2021)	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

SCV002130364

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 26, 2021)

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, SCV002130364.3

#	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. This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg18Glyfs*10) 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).

#	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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