NM_000249.4(MLH1):c.204C>G (p.Ile68Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 2022
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:: RCV001284503.6

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001470334	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Oct 31, 2022)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25435955, 25576899, 26467025
SCV001789229	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001470334

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Oct 31, 2022)

unknown

clinical testing

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

SCV001789229

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 1, 2022)

germline

clinical testing

Citation Link

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

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

Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing.

Kunstman JW, Juhlin CC, Goh G, Brown TC, Stenman A, Healy JM, Rubinstein JC, Choi M, Kiss N, Nelson-Williams C, Mane S, Rimm DL, Prasad ML, Höög A, Zedenius J, Larsson C, Korah R, Lifton RP, Carling T.

Hum Mol Genet. 2015 Apr 15;24(8):2318-29. doi: 10.1093/hmg/ddu749. Epub 2015 Jan 9.

PubMed [citation]

PMID:: 25576899
PMCID:: PMC4380073

See all PubMed Citations (3)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470334.2

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

Description

The frequency of this variant in the general population, 0.000004 (1/251396 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with rectal cancer (PMID: 25435955 (2015)) and thyroid cancer (PMID: 25576899 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 GeneDx, SCV001789229.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer (Vodicka et al., 2015); This variant is associated with the following publications: (PMID: 25576899, 22753075, 16083711, 21120944, 25435955)

#	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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine