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NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 20, 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:
RCV000565355.4

Allele description [Variation Report for NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)]

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 cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000669512Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 20, 2021) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Description and functional analysis of a novel in frame mutation linked to hereditary non-polyposis colorectal cancer.

Raevaara TE, Timoharju T, Lönnqvist KE, Kariola R, Steinhoff M, Hofstra RM, Mangold E, Vos YJ, Nyström-Lahti M.

J Med Genet. 2002 Oct;39(10):747-50. No abstract available.

PubMed [citation]
PMID:
12362032
PMCID:
PMC1734999

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
See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000669512.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

The c.213_215delAGA pathogenic mutation (also known as p.E71del) is located in coding exon 3 of the MLH1 gene. This pathogenic mutation results from an in-frame AGA deletion of three nucleotides between nucleotide positions 213 and 215, resulting in the in frame deletion of one amino acid (glutamate) at codon 71. This mutation has been reported in numerous individuals with Lynch syndrome (Chong G et al, Hum. Mutat. 2009 Aug; 30(8):E797-812; Kansikas M et al, Hum. Mutat. 2011 Jan; 32(1):107-15; McVety S et al, J. Med. Genet. 2006 Feb; 43(2):153-6; Mangold E et al, J. Pathol. 2005 Dec; 207(4):385-95; Overbeek LI et al, Br. J. Cancer 2007 May; 96(10):1605-12; Raevaara TE et al, Gastroenterology 2005 Aug; 129(2):537-49). cDNA sequencing indicated that this alteration causes exon 3 skipping during mRNA splicing, suggesting the presence of an exon splicing enhancer (ESE) at the 5' end of exon 3, and inclusion of exon 3 in the mRNA is ESE dependent (McVety S et al. J Med Genet. 2006 Feb;43(2):153-6). Further, multiple functional analyses of this mutation have shown significantly reduced DNA repair efficiency compared to wild type (Raevaara et al. J Med Genet. 2002 Oct;39(10):747-50; Raevaara et al. Gastroenterology. 2005 Aug;129(2):537-49; Ou et al. Hum Mutat. 2007 Nov;28(11):1047-54; Kansikas et al. Hum Mutat. 2011 Jan;32(1):107-15). Of note, this alteration is also designated as c.209_211delAAG and c.211_213delGAA in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024