NM_000249.4(MLH1):c.184C>T (p.Gln62Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 7, 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:: RCV000254916.16

Allele description [Variation Report for NM_000249.4(MLH1):c.184C>T (p.Gln62Ter)]

NM_000249.4(MLH1):c.184C>T (p.Gln62Ter)

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.184C>T (p.Gln62Ter)

HGVS:

NC_000003.12:g.36996686C>T
NG_007109.2:g.8337C>T
NG_008418.1:g.1619G>A
NM_000249.4:c.184C>TMANE SELECT
NM_001167617.3:c.-106C>T
NM_001167618.3:c.-540C>T
NM_001167619.3:c.-448C>T
NM_001258271.2:c.184C>T
NM_001258273.2:c.-517+3023C>T
NM_001258274.3:c.-685C>T
NM_001354615.2:c.-443C>T
NM_001354616.2:c.-448C>T
NM_001354617.2:c.-540C>T
NM_001354618.2:c.-540C>T
NM_001354619.2:c.-540C>T
NM_001354620.2:c.-106C>T
NM_001354621.2:c.-633C>T
NM_001354622.2:c.-746C>T
NM_001354623.2:c.-723+2796C>T
NM_001354624.2:c.-643C>T
NM_001354625.2:c.-546C>T
NM_001354626.2:c.-643C>T
NM_001354627.2:c.-643C>T
NM_001354628.2:c.184C>T
NM_001354629.2:c.184C>T
NM_001354630.2:c.184C>T
NP_000240.1:p.Gln62Ter
NP_000240.1:p.Gln62Ter
NP_001245200.1:p.Gln62Ter
NP_001341557.1:p.Gln62Ter
NP_001341558.1:p.Gln62Ter
NP_001341559.1:p.Gln62Ter
LRG_216t1:c.184C>T
LRG_216:g.8337C>T
LRG_216p1:p.Gln62Ter
NC_000003.11:g.37038177C>T
NM_000249.3:c.184C>T
p.Gln62*

Protein change:

Q62*

Links:

dbSNP: rs63751428

NCBI 1000 Genomes Browser:

rs63751428

Molecular consequence:

NM_001167617.3:c.-106C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-448C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-685C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-443C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-448C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-106C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-633C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-746C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3023C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2796C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Carex banksii isolate spm00007406 maturase K (matK) gene, partial cds; chloroplast
gi|1878290475|gb|MN763839.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321894	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 14, 2017)	germline	clinical testing	Citation Link,
SCV002821173	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2022)	germline	clinical testing	Citation Link,
SCV004220855	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jul 7, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20587412, 16451135, 16216036, 15849733, 12362047, 10323887, 9298827, 8521398, 7704024, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321894

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 14, 2017)

germline

clinical testing

Citation Link,

SCV002821173

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Dec 1, 2022)

germline

clinical testing

Citation Link,

SCV004220855

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Jul 7, 2023)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	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

Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.

Sjursen W, Haukanes BI, Grindedal EM, Aarset H, Stormorken A, Engebretsen LF, Jonsrud C, Bjørnevoll I, Andresen PA, Ariansen S, Lavik LA, Gilde B, Bowitz-Lothe IM, Maehle L, Møller P.

J Med Genet. 2010 Sep;47(9):579-85. doi: 10.1136/jmg.2010.077677. Epub 2010 Jun 28.

PubMed [citation]

PMID:: 20587412
PMCID:: PMC2976029

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000321894.6

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

Description

This variant is denoted MLH1 c.184C>T at the cDNA level and p.Gln62Ter (Q62X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple families meeting Amsterdam Criteria and/or Bethesda Guidelines for Lynch syndrome (Liu 1995, Mangold 2005, Sjursen 2010) and is considered pathogenic.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002821173.14

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

Description

MLH1: PVS1, PM2

#	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		2	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220855.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The MLH1 c.184C>T (p.Gln62*) variant causes the premature termination of MLH1 protein synthesis. This variant has been reported in the published literature in several affected individuals and families with colorectal cancer/Lynch Syndrome (PMIDs: 7704024 (1995), 8521398 (1995), 9298827 (1997), 10323887 (1999), 12362047 (2002), 15849733 (2005), 16216036 (2005), 16451135 (2006), and 20587412 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

#	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

Last Updated: Oct 20, 2024

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