NM_000249.4(MLH1):c.-7C>T AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Aug 15, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000115448.24

Allele description [Variation Report for NM_000249.4(MLH1):c.-7C>T]

NM_000249.4(MLH1):c.-7C>T

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.-7C>T

HGVS:

NC_000003.12:g.36993541C>T
NG_007109.2:g.5192C>T
NG_008418.1:g.4764G>A
NM_000249.4:c.-7C>TMANE SELECT
NM_001167617.3:c.-523C>T
NM_001167618.3:c.-952C>T
NM_001167619.3:c.-865C>T
NM_001258271.2:c.-7C>T
NM_001258273.2:c.-639C>T
NM_001258274.3:c.-1102C>T
NM_001354615.2:c.-633C>T
NM_001354616.2:c.-633C>T
NM_001354617.2:c.-725C>T
NM_001354618.2:c.-957C>T
NM_001354619.2:c.-1081C>T
NM_001354620.2:c.-291C>T
NM_001354621.2:c.-1050C>T
NM_001354622.2:c.-1163C>T
NM_001354623.2:c.-1072C>T
NM_001354624.2:c.-833C>T
NM_001354625.2:c.-731C>T
NM_001354626.2:c.-828C>T
NM_001354627.2:c.-1060C>T
NM_001354628.2:c.-7C>T
NM_001354629.2:c.-7C>T
NM_001354630.2:c.-7C>T
LRG_216t1:c.-7C>T
LRG_216:g.5192C>T
NC_000003.10:g.37010036C>T
NC_000003.11:g.37035032C>T
NM_000249.3:c.-7C>T

Links:

dbSNP: rs104894994

NCBI 1000 Genomes Browser:

rs104894994

Molecular consequence:

NM_000249.4:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167617.3:c.-523C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-952C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-865C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258271.2:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-639C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1102C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-633C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-633C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-725C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-957C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1081C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-291C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-1050C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1163C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-1072C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-833C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-731C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-828C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-1060C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354628.2:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354630.2:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339157	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Mar 5, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24689082, 27601186, 26888055, 25762362, 16963262, 29472279 Citation Link,
SCV002064693	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002552411	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848207	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Aug 10, 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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes.

Hansen MF, Neckmann U, Lavik LA, Vold T, Gilde B, Toft RK, Sjursen W.

Mol Genet Genomic Med. 2014 Mar;2(2):186-200. doi: 10.1002/mgg3.62. Epub 2014 Jan 21.

PubMed [citation]

PMID:: 24689082
PMCID:: PMC3960061

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: MLH1 c.-7C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0013 in 251462 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.8- fold the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00071), strongly suggesting that the variant is benign. c.-7C>T has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer (examples-Hesson_2015, Lagerstedt-Robinson_2016). The variant has also been detected in individuals reported to have hereditary prostate cancer (Fredriksson_2006) and non-HNPCC cancer phenotypes (Morak_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. One publication reports experimental evidence suggesting that the variant results in a 50% reduction in MLH1 expression,however, does not allow convincing conclusions about the variant effect (Hesson_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002064693.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002552411.4

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848207.1

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

Description

The c.-7C>T variant in MLH1 is classified as benign because it has been identified in 0.80% (202/25118, 2 homozygotes) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Identified in 2 families with this variant and suggested a partial loss of MLH1 expression (Hesson 2015 PMID:25762362). ACMG/AMP Criteria applied: BA1.

#	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: Apr 20, 2024

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