NM_000249.4(MLH1):c.67del (p.Glu23fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 6, 2022
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:: RCV000817865.6

Allele description [Variation Report for NM_000249.4(MLH1):c.67del (p.Glu23fs)]

NM_000249.4(MLH1):c.67del (p.Glu23fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.67del (p.Glu23fs)

HGVS:

NC_000003.12:g.36993614del
NG_007109.2:g.5265del
NG_008418.1:g.4695del
NM_000249.4:c.67delMANE SELECT
NM_001167617.3:c.-450del
NM_001167618.3:c.-879del
NM_001167619.3:c.-792del
NM_001258271.2:c.67del
NM_001258273.2:c.-566del
NM_001258274.3:c.-1029del
NM_001354615.2:c.-560del
NM_001354616.2:c.-560del
NM_001354617.2:c.-652del
NM_001354618.2:c.-884del
NM_001354619.2:c.-1008del
NM_001354620.2:c.-218del
NM_001354621.2:c.-977del
NM_001354622.2:c.-1090del
NM_001354623.2:c.-999del
NM_001354624.2:c.-760del
NM_001354625.2:c.-658del
NM_001354626.2:c.-755del
NM_001354627.2:c.-987del
NM_001354628.2:c.67del
NM_001354629.2:c.67del
NM_001354630.2:c.67del
NP_000240.1:p.Glu23fs
NP_001245200.1:p.Glu23fs
NP_001341557.1:p.Glu23fs
NP_001341558.1:p.Glu23fs
NP_001341559.1:p.Glu23fs
LRG_216:g.5265del
NC_000003.11:g.37035101del
NC_000003.11:g.37035105del
NM_000249.3:c.67delG

Protein change:

E23fs

Links:

dbSNP: rs63750822

NCBI 1000 Genomes Browser:

rs63750822

Molecular consequence:

NM_001167617.3:c.-450del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-879del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-792del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-566del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1029del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-560del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-560del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-652del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-884del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1008del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-218del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-977del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1090del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-999del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-760del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-658del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-755del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-987del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.67del - 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
SCV000958448	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 6, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24362816, 15342696, 15713769, 16451135, 18566915, 19224586, 25081409, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000958448

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 6, 2022)

germline

clinical testing

PubMed (8)
[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

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

BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.

Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espín E, Armengol M, Hamelin R, Yamamoto H, Hofstra RM, Seruca R, Lindblom A, Peltomäki P, Thibodeau SN, Aaltonen LA, Schwartz S Jr.

J Med Genet. 2004 Sep;41(9):664-8.

PubMed [citation]

PMID:: 15342696
PMCID:: PMC1735885

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958448.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Glu23Lysfs*13) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90332). This variant is also known as c.63del and c.66delG. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15342696, 15713769, 16451135, 18566915, 19224586, 25081409). This variant is not present in population databases (gnomAD no frequency).

#	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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