NM_000249.4(MLH1):c.110A>G (p.Glu37Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 22, 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:: RCV000214021.4

Allele description [Variation Report for NM_000249.4(MLH1):c.110A>G (p.Glu37Gly)]

NM_000249.4(MLH1):c.110A>G (p.Glu37Gly)

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.110A>G (p.Glu37Gly)

HGVS:

NC_000003.12:g.36993657A>G
NG_007109.2:g.5308A>G
NG_008418.1:g.4648T>C
NM_000249.4:c.110A>GMANE SELECT
NM_001167617.3:c.-407A>G
NM_001167618.3:c.-836A>G
NM_001167619.3:c.-749A>G
NM_001258271.2:c.110A>G
NM_001258273.2:c.-523A>G
NM_001258274.3:c.-986A>G
NM_001354615.2:c.-517A>G
NM_001354616.2:c.-517A>G
NM_001354617.2:c.-609A>G
NM_001354618.2:c.-841A>G
NM_001354619.2:c.-965A>G
NM_001354620.2:c.-175A>G
NM_001354621.2:c.-934A>G
NM_001354622.2:c.-1047A>G
NM_001354623.2:c.-956A>G
NM_001354624.2:c.-717A>G
NM_001354625.2:c.-615A>G
NM_001354626.2:c.-712A>G
NM_001354627.2:c.-944A>G
NM_001354628.2:c.110A>G
NM_001354629.2:c.110A>G
NM_001354630.2:c.110A>G
NP_000240.1:p.Glu37Gly
NP_000240.1:p.Glu37Gly
NP_001245200.1:p.Glu37Gly
NP_001341557.1:p.Glu37Gly
NP_001341558.1:p.Glu37Gly
NP_001341559.1:p.Glu37Gly
LRG_216t1:c.110A>G
LRG_216:g.5308A>G
LRG_216p1:p.Glu37Gly
NC_000003.11:g.37035148A>G
NM_000249.3:c.110A>G

Protein change:

E37G

Links:

dbSNP: rs876658410

NCBI 1000 Genomes Browser:

rs876658410

Molecular consequence:

NM_001167617.3:c.-407A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-836A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-749A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-523A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-986A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-517A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-517A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-609A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-841A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-965A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-175A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-934A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1047A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-956A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-717A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-615A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-712A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-944A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.110A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.110A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.110A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.110A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.110A>G - 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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Homo sapiens DNA cross-link repair 1A (PSO2 homolog, S. cerevisiae), mRNA (cDNA clone MGC:5167 IMAGE:3048375), complete cds
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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000273578	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12624141, 20233461, 27432916 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273578

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 22, 2022)

germline

clinical testing

PubMed (3)
[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

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]

PMID:: 12624141
PMCID:: PMC1735402

Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis.

Pigatto F, Bateman A, Bunyan D, Strike P, Wilkins E, Curtis C, Duncan P, May D, Nugent K, Eccles D.

Hered Cancer Clin Pract. 2004 Nov 15;2(4):175-84. doi: 10.1186/1897-4287-2-4-175.

PubMed [citation]

PMID:: 20233461
PMCID:: PMC2840004

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000273578.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.E37G pathogenic mutation (also known as c.110A>G), located in coding exon 1 of the MLH1 gene, results from an A to G substitution at nucleotide position 110. The glutamic acid at codon 37 is replaced by glycine, an amino acid with similar properties. This variant has been reported in individuals meeting Amsterdam criteria for Lynch syndrome; some also have Lynch tumors demonstrating loss of MLH1 on immunohistochemistry and high microsatellite instability (de Rosa N et al. J Clin Oncol, 2016 09;34:3039-46; Ambry internal data). Another alteration at the same codon, p.E37Q (c.109G>C), has been detected in an individual meeting Amsterdam criteria for Lynch syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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: Sep 29, 2024

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