NM_000249.4(MLH1):c.178C>T (p.Gln60Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 26, 2019
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:: RCV001181516.5

Allele description [Variation Report for NM_000249.4(MLH1):c.178C>T (p.Gln60Ter)]

NM_000249.4(MLH1):c.178C>T (p.Gln60Ter)

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.178C>T (p.Gln60Ter)

HGVS:

NC_000003.12:g.36996680C>T
NG_007109.2:g.8331C>T
NG_008418.1:g.1625G>A
NM_000249.4:c.178C>TMANE SELECT
NM_001167617.3:c.-112C>T
NM_001167618.3:c.-546C>T
NM_001167619.3:c.-454C>T
NM_001258271.2:c.178C>T
NM_001258273.2:c.-517+3017C>T
NM_001258274.3:c.-691C>T
NM_001354615.2:c.-449C>T
NM_001354616.2:c.-454C>T
NM_001354617.2:c.-546C>T
NM_001354618.2:c.-546C>T
NM_001354619.2:c.-546C>T
NM_001354620.2:c.-112C>T
NM_001354621.2:c.-639C>T
NM_001354622.2:c.-752C>T
NM_001354623.2:c.-723+2790C>T
NM_001354624.2:c.-649C>T
NM_001354625.2:c.-552C>T
NM_001354626.2:c.-649C>T
NM_001354627.2:c.-649C>T
NM_001354628.2:c.178C>T
NM_001354629.2:c.178C>T
NM_001354630.2:c.178C>T
NP_000240.1:p.Gln60Ter
NP_001245200.1:p.Gln60Ter
NP_001341557.1:p.Gln60Ter
NP_001341558.1:p.Gln60Ter
NP_001341559.1:p.Gln60Ter
LRG_216t1:c.178C>T
LRG_216:g.8331C>T
NC_000003.11:g.37038171C>T
NM_000249.3:c.178C>T

Protein change:

Q60*

Links:

dbSNP: rs2081170615

NCBI 1000 Genomes Browser:

rs2081170615

Molecular consequence:

NM_001167617.3:c.-112C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-454C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-691C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-449C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-454C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-112C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-639C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-752C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-649C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-552C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-649C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-649C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3017C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2790C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.178C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.178C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.178C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.178C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.178C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

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homo sapiens[Organism] AND CCDC19 AND (alive[prop]) (3)
Gene
uncharacterized protein LOC111477668 [Cucurbita maxima]
uncharacterized protein LOC111477668 [Cucurbita maxima]
gi|1280973467|ref|XP_022977309.1|

Protein
inorganic pyrophosphatase TTM2 isoform X2 [Cucumis melo]
inorganic pyrophosphatase TTM2 isoform X2 [Cucumis melo]
gi|659091356|ref|XP_008446505.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001346673	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002714436	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 6, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001346673

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 26, 2019)

germline

clinical testing

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

SCV002714436

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 6, 2017)

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

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 Color Diagnostics, LLC DBA Color Health, SCV001346673.2

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

Description

This variant changes 1 nucleotide in exon 2 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. 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

From Ambry Genetics, SCV002714436.2

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

Description

The p.Q60* pathogenic mutation (also known as c.178C>T), located in coding exon 2 of the MLH1 gene, results from a C to T substitution at nucleotide position 178. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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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