NM_000249.4(MLH1):c.1897-17C>G AND not specified

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Aug 15, 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:: RCV000115469.17

Allele description [Variation Report for NM_000249.4(MLH1):c.1897-17C>G]

NM_000249.4(MLH1):c.1897-17C>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.1897-17C>G

Other names:

IVS16-17C>G

HGVS:

NC_000003.12:g.37048500C>G
NG_007109.2:g.60151C>G
NM_000249.4:c.1897-17C>GMANE SELECT
NM_001167617.3:c.1603-17C>G
NM_001167618.3:c.1174-17C>G
NM_001167619.3:c.1174-17C>G
NM_001258271.2:c.1896+817C>G
NM_001258273.2:c.1174-17C>G
NM_001258274.3:c.1174-17C>G
NM_001354615.2:c.1174-17C>G
NM_001354616.2:c.1174-17C>G
NM_001354617.2:c.1174-17C>G
NM_001354618.2:c.1174-17C>G
NM_001354619.2:c.1174-17C>G
NM_001354620.2:c.1603-17C>G
NM_001354621.2:c.874-17C>G
NM_001354622.2:c.874-17C>G
NM_001354623.2:c.874-17C>G
NM_001354624.2:c.823-17C>G
NM_001354625.2:c.823-17C>G
NM_001354626.2:c.823-17C>G
NM_001354627.2:c.823-17C>G
NM_001354628.2:c.1897-404C>G
NM_001354629.2:c.1798-17C>G
NM_001354630.2:c.1732-17C>G
LRG_216t1:c.1897-17C>G
LRG_216:g.60151C>G
NC_000003.11:g.37089991C>G
NM_000249.3:c.1897-17C>G

Links:

dbSNP: rs2308316

NCBI 1000 Genomes Browser:

rs2308316

Molecular consequence:

NM_000249.4:c.1897-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.1603-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.1896+817C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.1174-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.1603-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.874-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.874-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.874-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.823-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.823-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.823-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.823-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.1897-404C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.1798-17C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.1732-17C>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000149378	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jan 4, 2018)	germline	clinical testing	Citation Link,
SCV000917655	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 6, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15520370, 18518984, 19526325 Citation Link,
SCV002550450	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149378

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jan 4, 2018)

germline

clinical testing

Citation Link,

SCV000917655

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jun 6, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002550450

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]

Help

Summary from all submissions

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

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF.

Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7. Epub 2004 Nov 1.

PubMed [citation]

PMID:: 15520370
PMCID:: PMC528777

Genome-wide survey of allele-specific splicing in humans.

Nembaware V, Lupindo B, Schouest K, Spillane C, Scheffler K, Seoighe C.

BMC Genomics. 2008 Jun 2;9:265. doi: 10.1186/1471-2164-9-265.

PubMed [citation]

PMID:: 18518984
PMCID:: PMC2427040

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000149378.7

#	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 considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917655.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: MLH1 c.1897-17C>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 277094 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00024 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1897-17C>G, has been reported in the literature in individuals affected with Lynch Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Berginc_2009, Fearnhead_2004, Kadiyska_2006). Co-occurrences with other pathogenic variants have been reported (MLH1 c.340_341dup, p.Ile115LeufsX22; MLH1 c.340dup, p.Thr114AsnfsX8), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory after 2014 without evidence for independent evaluation classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely 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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550450.4

#	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

Last Updated: Nov 10, 2024

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