NM_000249.3(MLH1):c.109G>A (p.Glu37Lys) AND Lynch syndrome

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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 5, 2013
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:: RCV000075110.2

Allele description

NM_000249.3(MLH1):c.109G>A (p.Glu37Lys)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.3(MLH1):c.109G>A (p.Glu37Lys)

HGVS:

NC_000003.12:g.36993656G>A
NG_007109.2:g.5307G>A
NG_008418.1:g.4649C>T
NM_000249.3:c.109G>A
NM_000249.3:c.109G>A
NM_001167617.2:c.-408G>A
NM_001167618.2:c.-837G>A
NM_001167619.2:c.-750G>A
NM_001258271.1:c.109G>A
NM_001258273.1:c.-524G>A
NM_001258274.2:c.-987G>A
NM_001354615.1:c.-518G>A
NM_001354616.1:c.-518G>A
NM_001354617.1:c.-610G>A
NM_001354618.1:c.-842G>A
NM_001354619.1:c.-966G>A
NM_001354620.1:c.-176G>A
NM_001354621.1:c.-935G>A
NM_001354622.1:c.-1048G>A
NM_001354623.1:c.-957G>A
NM_001354624.1:c.-718G>A
NM_001354625.1:c.-616G>A
NM_001354626.1:c.-713G>A
NM_001354627.1:c.-945G>A
NM_001354628.1:c.109G>A
NM_001354629.1:c.109G>A
NM_001354630.1:c.109G>A
NP_000240.1:p.Glu37Lys
NP_001245200.1:p.Glu37Lys
NP_001341557.1:p.Glu37Lys
NP_001341558.1:p.Glu37Lys
NP_001341559.1:p.Glu37Lys
LRG_216t1:c.109G>A
LRG_216:g.5307G>A
LRG_216p1:p.Glu37Lys
NC_000003.11:g.37035147G>A
P40692:p.Glu37Lys

Protein change:

E37K

Links:

UniProtKB: P40692#VAR_076339; dbSNP: rs63751012

NCBI 1000 Genomes Browser:

rs63751012

Molecular consequence:

NM_001167617.2:c.-408G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.2:c.-837G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.2:c.-750G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.1:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.2:c.-987G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.1:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.1:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.1:c.-610G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.1:c.-842G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.1:c.-966G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.1:c.-176G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.1:c.-935G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.1:c.-1048G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.1:c.-957G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.1:c.-718G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.1:c.-616G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.1:c.-713G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.1:c.-945G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.3:c.109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.1:c.109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.1:c.109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.1:c.109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.1:c.109G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome (HNPCC)
Synonyms:: Hereditary nonpolyposis colon cancer
Identifiers:: MedGen: C1333990; OMIM: PS120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106101	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Uncertain significance (Sep 5, 2013)	germline	research	Citation Link,
SCV000887392	University of Washington Department of Laboratory Medicine,University of Washington	criteria provided, single submitter (Shirts BH et al. (Am J Hum Genet 2018))	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

SCV000106101

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Uncertain significance
(Sep 5, 2013)

germline

research

Citation Link,

SCV000887392

University of Washington Department of Laboratory Medicine,University of Washington

criteria provided, single submitter

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

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	somatic	yes	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 International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106101.2

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

Description

Insufficient evidence

#	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 University of Washington Department of Laboratory Medicine,University of Washington, SCV000887392.1

#	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.109G>A has a 99.97% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with 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: Sep 23, 2019

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