NM_000249.4(MLH1):c.208-3C>G AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 30, 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:: RCV000160554.5

Allele description [Variation Report for NM_000249.4(MLH1):c.208-3C>G]

NM_000249.4(MLH1):c.208-3C>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.208-3C>G

HGVS:

NC_000003.12:g.37000952C>G
NG_007109.2:g.12603C>G
NM_000249.4:c.208-3C>GMANE SELECT
NM_001167617.3:c.-82-3C>G
NM_001167618.3:c.-516-3C>G
NM_001167619.3:c.-424-3C>G
NM_001258271.2:c.208-3C>G
NM_001258273.2:c.-516-3C>G
NM_001258274.3:c.-516-3C>G
NM_001354615.2:c.-419-3C>G
NM_001354616.2:c.-424-3C>G
NM_001354617.2:c.-516-3C>G
NM_001354618.2:c.-516-3C>G
NM_001354619.2:c.-516-3C>G
NM_001354620.2:c.-82-3C>G
NM_001354621.2:c.-609-3C>G
NM_001354622.2:c.-722-3C>G
NM_001354623.2:c.-722-3C>G
NM_001354624.2:c.-619-3C>G
NM_001354625.2:c.-522-3C>G
NM_001354626.2:c.-619-3C>G
NM_001354627.2:c.-619-3C>G
NM_001354628.2:c.208-3C>G
NM_001354629.2:c.208-3449C>G
NM_001354630.2:c.208-3C>G
LRG_216t1:c.208-3C>G
LRG_216:g.12603C>G
NC_000003.11:g.37042443C>G
NM_000249.3:c.208-3C>G

Links:

dbSNP: rs267607720

NCBI 1000 Genomes Browser:

rs267607720

Molecular consequence:

NM_000249.4:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.-82-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.-424-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-419-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-424-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.-82-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.-609-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.-722-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-722-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-522-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.208-3449C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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spindlin interactor and repressor of chromatin-binding protein isoform X5 [Homo ...
spindlin interactor and repressor of chromatin-binding protein isoform X5 [Homo sapiens]
gi|2462523137|ref|XP_054223747.1|

Protein
Homo sapiens cDNA clone IMAGE:40120714, containing frame-shift errors
Homo sapiens cDNA clone IMAGE:40120714, containing frame-shift errors
gi|113197841|gb|BC121127.1|

Nucleotide
PREDICTED: Homo sapiens spindlin interactor and repressor of chromatin binding (...
PREDICTED: Homo sapiens spindlin interactor and repressor of chromatin binding (SPINDOC), transcript variant X5, mRNA
gi|2462523136|ref|XM_054367772.1|

Nucleotide
Homo sapiens mRNA for KIAA1987 protein
Homo sapiens mRNA for KIAA1987 protein
gi|18916905|dbj|AB075867.1|

Nucleotide
Human PAX-3-FKHR gene fusion mRNA, partial cds
Human PAX-3-FKHR gene fusion mRNA, partial cds
gi|435418|gb|U02308.1|HSU02308

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211132	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (May 30, 2023)	germline	clinical testing	Citation Link,
SCV004220869	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (May 19, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25980754, 29887214, 26681312, 15991306, 19267393, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000211132

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(May 30, 2023)

germline

clinical testing

Citation Link,

SCV004220869

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(May 19, 2023)

unknown

clinical testing

PubMed (6)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S.

Gastroenterology. 2015 Sep;149(3):604-13.e20. doi: 10.1053/j.gastro.2015.05.006. Epub 2015 May 14.

PubMed [citation]

PMID:: 25980754
PMCID:: PMC4550537

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

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000211132.10

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

Description

Intronic variant demonstrated to result in an in-frame deletion of exon 3 (Arnold et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 26681312, 25980754, 28765196, 30787465, 29345684, 29887214, 31997046, 19267393, 15991306)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220869.1

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

Description

The MLH1 c.208-3C>G variant (also known as IVS2-3C>G) has been reported in the published literature in individuals and families affected with a Lynch syndrome associated cancer and/or polyps including colorectal cancer (PMID: 15991306 (2005), 19267393 (2009), 25980754 (2015), 26681312 (2015)). Functional studies report this variant results in the in-frame deletion of exon 3 (PMID: 15991306 (2005), 19267393 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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