NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del) AND Hereditary nonpolyposis colorectal neoplasms

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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 27, 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:: RCV000698898.6

Allele description

NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)

HGVS:

NC_000003.12:g.37000957AGA[1]
NG_007109.2:g.12608AGA[1]
NM_000249.4:c.210AGA[1]MANE SELECT
NM_001167617.3:c.-80AGA[1]
NM_001167618.3:c.-514AGA[1]
NM_001167619.3:c.-422AGA[1]
NM_001258271.2:c.210AGA[1]
NM_001258273.2:c.-514AGA[1]
NM_001258274.3:c.-514AGA[1]
NM_001354615.2:c.-417AGA[1]
NM_001354616.2:c.-422AGA[1]
NM_001354617.2:c.-514AGA[1]
NM_001354618.2:c.-514AGA[1]
NM_001354619.2:c.-514AGA[1]
NM_001354620.2:c.-80AGA[1]
NM_001354621.2:c.-607AGA[1]
NM_001354622.2:c.-720AGA[1]
NM_001354623.2:c.-720AGA[1]
NM_001354624.2:c.-617AGA[1]
NM_001354625.2:c.-520AGA[1]
NM_001354626.2:c.-617AGA[1]
NM_001354627.2:c.-617AGA[1]
NM_001354628.2:c.210AGA[1]
NM_001354629.2:c.208-3441_208-3439del
NM_001354630.2:c.210AGA[1]
NP_000240.1:p.Glu71del
NP_001245200.1:p.Glu71del
NP_001341557.1:p.Glu71del
NP_001341559.1:p.Glu71del
LRG_216t1:c.213_215del
LRG_216:g.12608AGA[1]
NC_000003.11:g.37042447_37042449del
NC_000003.11:g.37042448AGA[1]
NM_000249.3:c.213_215del
NM_000249.3:c.213_215delAGA
NM_000249.4:c.213_215delMANE SELECT

Protein change:

E71del

Links:

LOVD 3: MLH1_000141; OMIM: 120436.0023; dbSNP: rs63751642

NCBI 1000 Genomes Browser:

rs63751642

Molecular consequence:

NM_001167617.3:c.-80AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-422AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-417AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-422AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-514AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-80AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-607AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-720AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-720AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-617AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-520AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-617AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-617AGA[1] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.210AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258271.2:c.210AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354628.2:c.210AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354630.2:c.210AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354629.2:c.208-3441_208-3439del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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glyceraldehyde 3-phosphate dehydrogenase, partial [Almutaster pauciflorus]
glyceraldehyde 3-phosphate dehydrogenase, partial [Almutaster pauciflorus]
gi|197700621|gb|ACH72246.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000827588	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15923275, 18561205, 16083711, 12362032, 16216036, 17453009, 19459153, 23896635, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000827588

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 27, 2023)

germline

clinical testing

PubMed (9)
[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

Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.

McVety S, Li L, Gordon PH, Chong G, Foulkes WD.

J Med Genet. 2006 Feb;43(2):153-6. Epub 2005 May 27.

PubMed [citation]

PMID:: 15923275
PMCID:: PMC2564635

A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.

Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frébourg T, Tosi M.

Hum Mutat. 2008 Dec;29(12):1412-24. doi: 10.1002/humu.20796.

PubMed [citation]

PMID:: 18561205

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000827588.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant, c.213_215del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Glu71del), but otherwise preserves the integrity of the reading frame. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15923275, 18561205, 23896635). Experimental studies have shown that this variant affects MLH1 function (PMID: 12362032, 16083711). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90067). This variant is also known as 71del and c.209_211delAAG in the literature. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12362032, 16216036, 17453009, 19459153, 23896635). It has also been observed to segregate with disease in related individuals.

#	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 16, 2024

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