NM_000249.4(MLH1):c.1745T>A (p.Leu582His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 21, 2016
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:: RCV002401483.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1745T>A (p.Leu582His)]

NM_000249.4(MLH1):c.1745T>A (p.Leu582His)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1745T>A (p.Leu582His)

HGVS:

NC_000003.12:g.37047532T>A
NG_007109.2:g.59183T>A
NM_000249.4:c.1745T>AMANE SELECT
NM_001167617.3:c.1451T>A
NM_001167618.3:c.1022T>A
NM_001167619.3:c.1022T>A
NM_001258271.2:c.1745T>A
NM_001258273.2:c.1022T>A
NM_001258274.3:c.1022T>A
NM_001354615.2:c.1022T>A
NM_001354616.2:c.1022T>A
NM_001354617.2:c.1022T>A
NM_001354618.2:c.1022T>A
NM_001354619.2:c.1022T>A
NM_001354620.2:c.1451T>A
NM_001354621.2:c.722T>A
NM_001354622.2:c.722T>A
NM_001354623.2:c.722T>A
NM_001354624.2:c.671T>A
NM_001354625.2:c.671T>A
NM_001354626.2:c.671T>A
NM_001354627.2:c.671T>A
NM_001354628.2:c.1745T>A
NM_001354629.2:c.1646T>A
NM_001354630.2:c.1732-985T>A
NP_000240.1:p.Leu582His
NP_000240.1:p.Leu582His
NP_001161089.1:p.Leu484His
NP_001161090.1:p.Leu341His
NP_001161091.1:p.Leu341His
NP_001245200.1:p.Leu582His
NP_001245202.1:p.Leu341His
NP_001245203.1:p.Leu341His
NP_001341544.1:p.Leu341His
NP_001341545.1:p.Leu341His
NP_001341546.1:p.Leu341His
NP_001341547.1:p.Leu341His
NP_001341548.1:p.Leu341His
NP_001341549.1:p.Leu484His
NP_001341550.1:p.Leu241His
NP_001341551.1:p.Leu241His
NP_001341552.1:p.Leu241His
NP_001341553.1:p.Leu224His
NP_001341554.1:p.Leu224His
NP_001341555.1:p.Leu224His
NP_001341556.1:p.Leu224His
NP_001341557.1:p.Leu582His
NP_001341558.1:p.Leu549His
LRG_216t1:c.1745T>A
LRG_216:g.59183T>A
LRG_216p1:p.Leu582His
NC_000003.11:g.37089023T>A
NM_000249.3:c.1745T>A

Protein change:

L224H

Molecular consequence:

NM_001354630.2:c.1732-985T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1745T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1451T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1745T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1022T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1451T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.722T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.722T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.722T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.671T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.671T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.671T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.671T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1745T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1646T>A - missense variant - [Sequence Ontology: SO:0001583]

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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mitogen-activated protein kinase 15 [Rattus norvegicus]
mitogen-activated protein kinase 15 [Rattus norvegicus]
gi|27545428|ref|NP_775453.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002710290	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 21, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002710290

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 21, 2016)

germline

clinical testing

Citation Link

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

Details of each submission

From Ambry Genetics, SCV002710290.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.L582H pathogenic mutation (also known as c.1745T>A), located in coding exon 16 of the MLH1 gene, results from a T to A substitution at nucleotide position 1745. The leucine at codon 582 is replaced by histidine, an amino acid with similar properties. This alteration was reported in several families meeting Amsterdam II criteria (Ambry internal data; Universal Mutation Database [available from www.umd.be]). Based on internal assessment, this alteration destabilizes the fold of the C-terminal exonuclease domain, with magnitude of destabilization equal to or greater than that of nearby pathogenic alterations (Dombrovsky, L., et al., unpublished structure PDB: 3RBN). A different alteration at the same codon, p.L582P, has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson B et al. Hum Mutat. 2013 Jan;34(1):200-9; Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. The p.L582H alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: May 1, 2024

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