NM_000249.4(MLH1):c.1668-5T>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 15, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002397526.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1668-5T>G]

NM_000249.4(MLH1):c.1668-5T>G

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.1668-5T>G

HGVS:

NC_000003.12:g.37042263T>G
NG_007109.2:g.53914T>G
NM_000249.4:c.1668-5T>GMANE SELECT
NM_001167617.3:c.1374-5T>G
NM_001167618.3:c.945-5T>G
NM_001167619.3:c.945-5T>G
NM_001258271.2:c.1668-5T>G
NM_001258273.2:c.945-5T>G
NM_001258274.3:c.945-5T>G
NM_001354615.2:c.945-5T>G
NM_001354616.2:c.945-5T>G
NM_001354617.2:c.945-5T>G
NM_001354618.2:c.945-5T>G
NM_001354619.2:c.945-5T>G
NM_001354620.2:c.1374-5T>G
NM_001354621.2:c.645-5T>G
NM_001354622.2:c.645-5T>G
NM_001354623.2:c.645-5T>G
NM_001354624.2:c.594-5T>G
NM_001354625.2:c.594-5T>G
NM_001354626.2:c.594-5T>G
NM_001354627.2:c.594-5T>G
NM_001354628.2:c.1668-5T>G
NM_001354629.2:c.1569-5T>G
NM_001354630.2:c.1668-5T>G
LRG_216t1:c.1668-5T>G
LRG_216:g.53914T>G
NC_000003.11:g.37083754T>G
NM_000249.3:c.1668-5T>G

Links:

dbSNP: rs1559578408

NCBI 1000 Genomes Browser:

rs1559578408

Molecular consequence:

NM_000249.4:c.1668-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.1374-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.1668-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.945-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.1374-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.645-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.645-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.645-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.594-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.594-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.594-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.594-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.1668-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.1569-5T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.1668-5T>G - intron variant - [Sequence Ontology: SO:0001627]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002709213	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002709213

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 15, 2020)

germline

clinical testing

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

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

Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Shirts BH, Konnick EQ, Upham S, Walsh T, Ranola JMO, Jacobson AL, King MC, Pearlman R, Hampel H, Pritchard CC.

Am J Hum Genet. 2018 Jul 5;103(1):19-29. doi: 10.1016/j.ajhg.2018.05.001. Epub 2018 Jun 7.

PubMed [citation]

PMID:: 29887214
PMCID:: PMC6035155

Details of each submission

From Ambry Genetics, SCV002709213.2

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

Description

The c.1668-5T>G intronic variant results from a T to G substitution 5 nucleotides upstream from coding exon 15 in the MLH1 gene. This nucleotide position is well conserved in available vertebrate species. This alteration was identified in a tumor with loss of heterozygosity (LOH) at MLH1 locus (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 1, 2024

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