NM_000249.4(MLH1):c.200G>A (p.Gly67Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000132445.10

Allele description [Variation Report for NM_000249.4(MLH1):c.200G>A (p.Gly67Glu)]

NM_000249.4(MLH1):c.200G>A (p.Gly67Glu)

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.200G>A (p.Gly67Glu)

HGVS:

NC_000003.12:g.36996702G>A
NG_007109.2:g.8353G>A
NG_008418.1:g.1603C>T
NM_000249.4:c.200G>AMANE SELECT
NM_001167617.3:c.-90G>A
NM_001167618.3:c.-524G>A
NM_001167619.3:c.-432G>A
NM_001258271.2:c.200G>A
NM_001258273.2:c.-517+3039G>A
NM_001258274.3:c.-669G>A
NM_001354615.2:c.-427G>A
NM_001354616.2:c.-432G>A
NM_001354617.2:c.-524G>A
NM_001354618.2:c.-524G>A
NM_001354619.2:c.-524G>A
NM_001354620.2:c.-90G>A
NM_001354621.2:c.-617G>A
NM_001354622.2:c.-730G>A
NM_001354623.2:c.-723+2812G>A
NM_001354624.2:c.-627G>A
NM_001354625.2:c.-530G>A
NM_001354626.2:c.-627G>A
NM_001354627.2:c.-627G>A
NM_001354628.2:c.200G>A
NM_001354629.2:c.200G>A
NM_001354630.2:c.200G>A
NP_000240.1:p.Gly67Glu
NP_000240.1:p.Gly67Glu
NP_001245200.1:p.Gly67Glu
NP_001341557.1:p.Gly67Glu
NP_001341558.1:p.Gly67Glu
NP_001341559.1:p.Gly67Glu
LRG_216t1:c.200G>A
LRG_216:g.8353G>A
LRG_216p1:p.Gly67Glu
NC_000003.11:g.37038193G>A
NM_000249.3:c.200G>A
NM_001167618.1:c.-524G>A
P40692:p.Gly67Glu
p.G67E

Protein change:

G67E; GLY67GLU

Links:

UniProtKB: P40692#VAR_038024; OMIM: 120436.0029; dbSNP: rs63749939

NCBI 1000 Genomes Browser:

rs63749939

Molecular consequence:

NM_001167617.3:c.-90G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-432G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-669G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-427G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-432G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-90G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-617G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-730G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-627G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-530G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-627G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-627G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3039G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2812G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.200G>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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Gm5934 predicted gene 5934 [Mus musculus]
Gm5934 predicted gene 5934 [Mus musculus]
Gene ID:546272

Gene
Gm5934 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187539	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16807412, 25617771, 26249686, 32659967 Citation Link,
SCV001734846	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187539

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 24, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001734846

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 5, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.

Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, Campbell H, Dunlop MG.

N Engl J Med. 2006 Jun 29;354(26):2751-63.

PubMed [citation]

PMID:: 16807412

Impact of an immunohistochemistry-based universal screening protocol for Lynch syndrome in endometrial cancer on genetic counseling and testing.

Frolova AI, Babb SA, Zantow E, Hagemann AR, Powell MA, Thaker PH, Gao F, Mutch DG.

Gynecol Oncol. 2015 Apr;137(1):7-13. doi: 10.1016/j.ygyno.2015.01.535. Epub 2015 Jan 21.

PubMed [citation]

PMID:: 25617771
PMCID:: PMC4380539

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000187539.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.G67E pathogenic mutation (also known as c.200G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 200. The glycine at codon 67 is replaced by glutamic acid, an amino acid with similar properties. This alteration is observed in several individuals whose Lynch-related tumors demonstrated high microsatellite instability and/or loss of MLH1 or MLH1 and PMS2 expression on immunohistochemistry (IHC), and MLH1 promoter hypermethylation was negative (Ambry internal data; Barnetson RA et al. Hum Mutat. 2008 Mar;29(3):367-74). This alteration segregated with disease in multiple colon cancer families, and in one family with many cancers that are atypical for Lynch syndrome (Barnetson RA et al. Hum Mutat. 2008 Mar;29(3):367-74; Clyne M et al. Br J Cancer. 2009 Jan 27;100(2):376-80). In vitro yeast studies indicated that G67E is stably expressed but showed inhibition of protein activity during MMR and was therefore categorized as a loss of function allele (Clyne M et al. Br J Cancer. 2009 Jan 27;100(2):376-80). Based on internal structural analysis using published crystal structures, p.G67E is anticipated to result in a significant decrease in structural stability (Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5; 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

From Color Diagnostics, LLC DBA Color Health, SCV001734846.1

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

Description

This missense variant replaces glycine with glutamic acid at codon 67 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein impairs DNA mismatch repair activity in yeast-based assays (PMID: 15475387, 19142183). This variant has been reported in individuals affected with colorectal cancer (PMID: 16807412, 18033691), endometrial cancer (PMID: 25617771), prostate cancer (PMID: 18033691), breast cancer (PMID: 18033691, 19142183, 32081490), uveal melanoma (PMID: 32081490), and leiomyosarcoma (PMID: 19142183, 32659967). It has also been reported that this variant segregates with Lynch syndrome-associated cancers in multiple families (PMID: 18033691). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as 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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