NM_000249.4(MLH1):c.204C>G (p.Ile68Met) AND Lynch syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 3, 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:: RCV000708913.4

Allele description [Variation Report for NM_000249.4(MLH1):c.204C>G (p.Ile68Met)]

NM_000249.4(MLH1):c.204C>G (p.Ile68Met)

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.204C>G (p.Ile68Met)

HGVS:

NC_000003.12:g.36996706C>G
NG_007109.2:g.8357C>G
NG_008418.1:g.1599G>C
NM_000249.4:c.204C>GMANE SELECT
NM_001167617.3:c.-86C>G
NM_001167618.3:c.-520C>G
NM_001167619.3:c.-428C>G
NM_001258271.2:c.204C>G
NM_001258273.2:c.-517+3043C>G
NM_001258274.3:c.-665C>G
NM_001354615.2:c.-423C>G
NM_001354616.2:c.-428C>G
NM_001354617.2:c.-520C>G
NM_001354618.2:c.-520C>G
NM_001354619.2:c.-520C>G
NM_001354620.2:c.-86C>G
NM_001354621.2:c.-613C>G
NM_001354622.2:c.-726C>G
NM_001354623.2:c.-723+2816C>G
NM_001354624.2:c.-623C>G
NM_001354625.2:c.-526C>G
NM_001354626.2:c.-623C>G
NM_001354627.2:c.-623C>G
NM_001354628.2:c.204C>G
NM_001354629.2:c.204C>G
NM_001354630.2:c.204C>G
NP_000240.1:p.Ile68Met
NP_000240.1:p.Ile68Met
NP_001245200.1:p.Ile68Met
NP_001341557.1:p.Ile68Met
NP_001341558.1:p.Ile68Met
NP_001341559.1:p.Ile68Met
LRG_216t1:c.204C>G
LRG_216:g.8357C>G
LRG_216p1:p.Ile68Met
NC_000003.11:g.37038197C>G
NM_000249.3:c.204C>G

Protein change:

I68M

Links:

dbSNP: rs780141938

NCBI 1000 Genomes Browser:

rs780141938

Molecular consequence:

NM_001167617.3:c.-86C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-520C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-428C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-665C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-423C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-428C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-520C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-520C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-520C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-86C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-613C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-726C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-623C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-526C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-623C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-623C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3043C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2816C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.204C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.204C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.204C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.204C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.204C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000837995	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004835252	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25435955, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000837995

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Jul 2, 2018)

unknown

clinical testing

Citation Link,

SCV004835252

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 2023)

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	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel c. 204 Ile68Met germline variant in exon 2 of the mutL homolog 1 gene in a colorectal cancer patient.

Vodicka P, Caja F, Vymetalkova V, Prochazka P, Vodickova L, Schwarzova L, Slyskova J, Kumar R, Schneiderova M.

Oncol Lett. 2015 Jan;9(1):183-186. Epub 2014 Nov 4.

PubMed [citation]

PMID:: 25435955
PMCID:: PMC4247117

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Mendelics, SCV000837995.2

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

#	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

From All of Us Research Program, National Institutes of Health, SCV004835252.1

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

Description

This missense variant replaces isoleucine with methionine at codon 68 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer but without the clinical features of Lynch syndrome (PMID: 25435955). This variant has been identified in 1/251396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.203T>G (p.Ile68Ser) and c.203T>A (p.Ile68Asn), are considered to be disease-causing (ClinVar variation ID: 820585, 90008), suggesting that this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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