NM_000249.4(MLH1):c.203T>G (p.Ile68Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 24, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001014185.4

Allele description [Variation Report for NM_000249.4(MLH1):c.203T>G (p.Ile68Ser)]

NM_000249.4(MLH1):c.203T>G (p.Ile68Ser)

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.203T>G (p.Ile68Ser)

HGVS:

NC_000003.12:g.36996705T>G
NG_007109.2:g.8356T>G
NG_008418.1:g.1600A>C
NM_000249.4:c.203T>GMANE SELECT
NM_001167617.3:c.-87T>G
NM_001167618.3:c.-521T>G
NM_001167619.3:c.-429T>G
NM_001258271.2:c.203T>G
NM_001258273.2:c.-517+3042T>G
NM_001258274.3:c.-666T>G
NM_001354615.2:c.-424T>G
NM_001354616.2:c.-429T>G
NM_001354617.2:c.-521T>G
NM_001354618.2:c.-521T>G
NM_001354619.2:c.-521T>G
NM_001354620.2:c.-87T>G
NM_001354621.2:c.-614T>G
NM_001354622.2:c.-727T>G
NM_001354623.2:c.-723+2815T>G
NM_001354624.2:c.-624T>G
NM_001354625.2:c.-527T>G
NM_001354626.2:c.-624T>G
NM_001354627.2:c.-624T>G
NM_001354628.2:c.203T>G
NM_001354629.2:c.203T>G
NM_001354630.2:c.203T>G
NP_000240.1:p.Ile68Ser
NP_001245200.1:p.Ile68Ser
NP_001341557.1:p.Ile68Ser
NP_001341558.1:p.Ile68Ser
NP_001341559.1:p.Ile68Ser
LRG_216t1:c.203T>G
LRG_216:g.8356T>G
NC_000003.11:g.37038196T>G
NM_000249.3:c.203T>G

Protein change:

I68S

Links:

dbSNP: rs63750281

NCBI 1000 Genomes Browser:

rs63750281

Molecular consequence:

NM_001167617.3:c.-87T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-521T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-429T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-666T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-424T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-429T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-521T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-521T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-521T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-87T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-614T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-727T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-624T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-527T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-624T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-624T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3042T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2815T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001174867	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 24, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15475387, 26249686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001174867

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 24, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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	clinical testing

Citations

PubMed

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome.

Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J.

Acta Crystallogr F Struct Biol Commun. 2015 Aug;71(Pt 8):981-5. doi: 10.1107/S2053230X15010183. Epub 2015 Jul 28.

PubMed [citation]

PMID:: 26249686
PMCID:: PMC4528928

Details of each submission

From Ambry Genetics, SCV001174867.4

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

Description

The p.I68S variant (also known as c.203T>G), located in coding exon 2 of the MLH1 gene, results from a T to G substitution at nucleotide position 203. The isoleucine at codon 68 is replaced by serine, an amino acid with dissimilar properties. This variant was identified in an individual whose colorectal tumor displayed loss of both MLH1/PMS2 expression on immunohistochemistry (IHC) and was negative for MLH1 promoter hypermethylation (Ambry internal data). In a yeast-based assay designed to measure mismatch repair (MMR) activity, this variant demonstrated a 34–66% loss-of-MMR function (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). Based on an internal structural analysis, this variant is anticipated to disrupt the ATP binding motif (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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

Last Updated: May 1, 2024

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