NM_000249.4(MLH1):c.182T>A (p.Ile61Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 19, 2018
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:: RCV002410518.2

Allele description [Variation Report for NM_000249.4(MLH1):c.182T>A (p.Ile61Asn)]

NM_000249.4(MLH1):c.182T>A (p.Ile61Asn)

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.182T>A (p.Ile61Asn)

HGVS:

NC_000003.12:g.36996684T>A
NG_007109.2:g.8335T>A
NG_008418.1:g.1621A>T
NM_000249.4:c.182T>AMANE SELECT
NM_001167617.3:c.-108T>A
NM_001167618.3:c.-542T>A
NM_001167619.3:c.-450T>A
NM_001258271.2:c.182T>A
NM_001258273.2:c.-517+3021T>A
NM_001258274.3:c.-687T>A
NM_001354615.2:c.-445T>A
NM_001354616.2:c.-450T>A
NM_001354617.2:c.-542T>A
NM_001354618.2:c.-542T>A
NM_001354619.2:c.-542T>A
NM_001354620.2:c.-108T>A
NM_001354621.2:c.-635T>A
NM_001354622.2:c.-748T>A
NM_001354623.2:c.-723+2794T>A
NM_001354624.2:c.-645T>A
NM_001354625.2:c.-548T>A
NM_001354626.2:c.-645T>A
NM_001354627.2:c.-645T>A
NM_001354628.2:c.182T>A
NM_001354629.2:c.182T>A
NM_001354630.2:c.182T>A
NP_000240.1:p.Ile61Asn
NP_000240.1:p.Ile61Asn
NP_001245200.1:p.Ile61Asn
NP_001341557.1:p.Ile61Asn
NP_001341558.1:p.Ile61Asn
NP_001341559.1:p.Ile61Asn
LRG_216t1:c.182T>A
LRG_216:g.8335T>A
LRG_216p1:p.Ile61Asn
NC_000003.11:g.37038175T>A
NM_000249.3:c.182T>A

Protein change:

I61N

Molecular consequence:

NM_001167617.3:c.-108T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-542T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-450T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-687T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-445T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-450T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-542T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-542T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-542T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-108T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-635T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-748T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-645T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-548T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-645T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-645T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3021T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2794T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.182T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.182T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.182T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.182T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.182T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002714644	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 19, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15475387, 26249686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002714644

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 19, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome.

Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J.

Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):981-5. doi: 10.1107/S2053230X15010183. Epub 2015 Jul 28.

PubMed [citation]

PMID:: 26249686
PMCID:: PMC4528928

Details of each submission

From Ambry Genetics, SCV002714644.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.I61N variant (also known as c.182T>A), located in coding exon 2 of the MLH1 gene, results from a T to A substitution at nucleotide position 182. The isoleucine at codon 61 is replaced by asparagine, an amino acid with dissimilar properties. In a functional assay using a prospective genetic screen with hybrid human-yeast MLH1 genes in yeast, this variant demonstrated a 34–66% loss-of-mismatch repair (MMR) function (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). Based on an internal structural assessment, this alteration results in local structural destabilization in the ATPase domain (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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