NM_000249.4(MLH1):c.156del (p.Glu53fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 20, 2023
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:: RCV000533345.7

Allele description [Variation Report for NM_000249.4(MLH1):c.156del (p.Glu53fs)]

NM_000249.4(MLH1):c.156del (p.Glu53fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.156del (p.Glu53fs)

HGVS:

NC_000003.12:g.36996658del
NG_007109.2:g.8309del
NG_008418.1:g.1649del
NM_000249.4:c.156delMANE SELECT
NM_001167617.3:c.-134del
NM_001167618.3:c.-568del
NM_001167619.3:c.-476del
NM_001258271.2:c.156del
NM_001258273.2:c.-517+2995del
NM_001258274.3:c.-713del
NM_001354615.2:c.-471del
NM_001354616.2:c.-476del
NM_001354617.2:c.-568del
NM_001354618.2:c.-568del
NM_001354619.2:c.-568del
NM_001354620.2:c.-134del
NM_001354621.2:c.-661del
NM_001354622.2:c.-774del
NM_001354623.2:c.-723+2768del
NM_001354624.2:c.-671del
NM_001354625.2:c.-574del
NM_001354626.2:c.-671del
NM_001354627.2:c.-671del
NM_001354628.2:c.156del
NM_001354629.2:c.156del
NM_001354630.2:c.156del
NP_000240.1:p.Glu53fs
NP_001245200.1:p.Glu53fs
NP_001341557.1:p.Glu53fs
NP_001341558.1:p.Glu53fs
NP_001341559.1:p.Glu53fs
LRG_216:g.8309del
NC_000003.11:g.37038147del
NC_000003.11:g.37038149del
NC_000003.12:g.36996658delA
NM_000249.3:c.156delA
NM_000249.4:c.156del
p.Glu53Argfs*4
p.Glu53ArgfsTer4

Protein change:

E53fs

Links:

dbSNP: rs63750028

NCBI 1000 Genomes Browser:

rs63750028

Molecular consequence:

NM_001167617.3:c.-134del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-476del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-713del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-471del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-476del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-568del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-134del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-661del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-774del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-671del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-574del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-671del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-671del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.156del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.-517+2995del - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2768del - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

Unknown function

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
SCV000625082	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28514183, 15713769, 24362816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625082

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 20, 2023)

germline

clinical testing

PubMed (4)
[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

Multigene Panel Testing Provides a New Perspective on Lynch Syndrome.

Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H.

J Clin Oncol. 2017 Aug 1;35(22):2568-2575. doi: 10.1200/JCO.2016.71.9260. Epub 2017 May 17.

PubMed [citation]

PMID:: 28514183
PMCID:: PMC7186580

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625082.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89793). This premature translational stop signal has been observed in individual(s) with MLH1-related conditions (PMID: 15713769, 24362816, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu53Argfs*4) 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: Nov 3, 2024

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