NM_000249.4(MLH1):c.200G>A (p.Gly67Glu) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 15, 2023
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:: RCV000216147.12

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279068	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 15, 2023)	germline	clinical testing	Citation Link,
SCV000691842	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV003821562	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 31, 2022)	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

SCV000279068

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 15, 2023)

germline

clinical testing

Citation Link,

SCV000691842

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Pathogenic

unknown

clinical testing

SCV003821562

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 31, 2022)

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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000279068.12

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Segregates with disease in several families meeting Amsterdam criteria, with tumor studies from some individuals demonstrating microsatellite instability (MSI) and/or loss of MLH1 protein expression (Terdiman et al., 2001; Barnetson et al., 2006; Barnetson et al., 2008; Clyne et al., 2009; Yu et al., 2009; Chubb et al., 2015; Frolova et al., 2015); This variant is associated with the following publications: (PMID: 20459533, 24878972, 23510156, 23741719, 16807412, 15475387, 19142183, 22290698, 22949387, 24362816, 11208710, 16995940, 17939062, 17192056, 19493351, 18033691, 25559809, 20068152, 20668451, 22516243, 29887214, 32081490, 30877237, 30787465, 25617771, 22753075, 16083711, 21120944)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000691842.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003821562.2

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

#	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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