NM_000249.4(MLH1):c.589-17T>A AND Hereditary nonpolyposis colorectal neoplasms

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 28, 2024
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:: RCV001855627.5

Allele description

NM_000249.4(MLH1):c.589-17T>A

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.589-17T>A

HGVS:

NC_000003.12:g.37011994T>A
NG_007109.2:g.23645T>A
NM_000249.4:c.589-17T>AMANE SELECT
NM_001167617.3:c.295-17T>A
NM_001167618.3:c.-135-17T>A
NM_001167619.3:c.-135-17T>A
NM_001258271.2:c.589-17T>A
NM_001258273.2:c.-135-17T>A
NM_001258274.3:c.-135-17T>A
NM_001354615.2:c.-135-17T>A
NM_001354616.2:c.-135-17T>A
NM_001354617.2:c.-135-17T>A
NM_001354618.2:c.-135-17T>A
NM_001354619.2:c.-135-17T>A
NM_001354620.2:c.295-17T>A
NM_001354621.2:c.-228-17T>A
NM_001354622.2:c.-341-17T>A
NM_001354623.2:c.-341-17T>A
NM_001354624.2:c.-238-17T>A
NM_001354625.2:c.-238-17T>A
NM_001354626.2:c.-238-17T>A
NM_001354627.2:c.-238-17T>A
NM_001354628.2:c.589-17T>A
NM_001354629.2:c.490-17T>A
NM_001354630.2:c.589-17T>A
LRG_216t1:c.589-17T>A
LRG_216:g.23645T>A
NC_000003.11:g.37053485T>A
NM_000249.3:c.589-17T>A

Links:

dbSNP: rs754180618

NCBI 1000 Genomes Browser:

rs754180618

Molecular consequence:

NM_000249.4:c.589-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.295-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.589-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.-135-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.295-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.-228-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.-341-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-341-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.-238-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-238-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-238-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-238-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.589-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.490-17T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.589-17T>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002316394	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24802709, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002316394

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 28, 2024)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns.

Borelli I, Casalis Cavalchini GC, Del Peschio S, Micheletti M, Venesio T, Sarotto I, Allavena A, Delsedime L, Barberis MA, Mandrile G, Berchialla P, Ogliara P, Bracco C, Pasini B.

Fam Cancer. 2014 Sep;13(3):401-13. doi: 10.1007/s10689-014-9726-3.

PubMed [citation]

PMID:: 24802709

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002316394.3

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

Description

This sequence change falls in intron 7 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 5 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs754180618, gnomAD 0.004%). This variant has been observed in individual(s) with colorectal cancer (PMID: 24802709). ClinVar contains an entry for this variant (Variation ID: 560784). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 24802709; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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