NM_000249.4(MLH1):c.440G>A (p.Gly147Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 4, 2020
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:: RCV002332456.2

Allele description [Variation Report for NM_000249.4(MLH1):c.440G>A (p.Gly147Glu)]

NM_000249.4(MLH1):c.440G>A (p.Gly147Glu)

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.440G>A (p.Gly147Glu)

HGVS:

NC_000003.12:g.37007050G>A
NG_007109.2:g.18701G>A
NM_000249.4:c.440G>AMANE SELECT
NM_001167617.3:c.146G>A
NM_001167618.3:c.-284G>A
NM_001167619.3:c.-192G>A
NM_001258271.2:c.440G>A
NM_001258273.2:c.-284G>A
NM_001258274.3:c.-284G>A
NM_001354615.2:c.-192G>A
NM_001354616.2:c.-192G>A
NM_001354617.2:c.-284G>A
NM_001354618.2:c.-284G>A
NM_001354619.2:c.-284G>A
NM_001354620.2:c.146G>A
NM_001354621.2:c.-377G>A
NM_001354622.2:c.-490G>A
NM_001354623.2:c.-490G>A
NM_001354624.2:c.-387G>A
NM_001354625.2:c.-295G>A
NM_001354626.2:c.-387G>A
NM_001354627.2:c.-387G>A
NM_001354628.2:c.440G>A
NM_001354629.2:c.341G>A
NM_001354630.2:c.440G>A
NP_000240.1:p.Gly147Glu
NP_000240.1:p.Gly147Glu
NP_001161089.1:p.Gly49Glu
NP_001245200.1:p.Gly147Glu
NP_001341549.1:p.Gly49Glu
NP_001341557.1:p.Gly147Glu
NP_001341558.1:p.Gly114Glu
NP_001341559.1:p.Gly147Glu
LRG_216t1:c.440G>A
LRG_216:g.18701G>A
LRG_216p1:p.Gly147Glu
NC_000003.11:g.37048541G>A
NM_000249.3:c.440G>A

Protein change:

G114E

Links:

dbSNP: rs1060500702

NCBI 1000 Genomes Browser:

rs1060500702

Molecular consequence:

NM_001167618.3:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-192G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-192G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-192G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-284G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-377G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-490G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-490G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-387G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-295G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-387G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-387G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.146G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.146G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.341G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.440G>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
SCV002627993	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 4, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002627993

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 4, 2020)

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, SCV002627993.2

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

Description

The p.G147E variant (also known as c.440G>A), located in coding exon 5 of the MLH1 gene, results from a G to A substitution at nucleotide position 440. The glycine at codon 147 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant has been identified as germline in an individual meeting Amsterdam criteria with MSI-H colorectal cancer also demonstrating loss of PMS2 and weak MLH1 staining by IHC. Somatic copy-neutral loss of heterozygosity (CN-LOH) of MLH1 was also identified in this individual's tumor (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been classified as likely 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 BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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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