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

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 21, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075517.6

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)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106518	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Likely pathogenic (Jun 21, 2019)	germline	curation	Citation Link,
SCV000887397	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts BH et al. (Am J Hum Genet 2018))	Likely pathogenic (May 1, 2018)	somatic	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

SCV000106518

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Likely pathogenic
(Jun 21, 2019)

germline

curation

Citation Link,

SCV000887397

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts BH et al. (Am J Hum Genet 2018))

Likely pathogenic
(May 1, 2018)

somatic

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	somatic	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation

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 International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106518.3

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

Description

Variant causes splicing aberration (not quantified) & 3 MSI-H tumours. Multifactorial likelihood analysis posterior probability 0.95-0.99.

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000887397.1

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

Description

MLH1 NM_000249.3:c.208-3C>G has a 97.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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

Last Updated: Jun 9, 2024

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