NM_000249.4(MLH1):c.224T>C (p.Ile75Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 18, 2018
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:: RCV000222796.6

Allele description [Variation Report for NM_000249.4(MLH1):c.224T>C (p.Ile75Thr)]

NM_000249.4(MLH1):c.224T>C (p.Ile75Thr)

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.224T>C (p.Ile75Thr)

HGVS:

NC_000003.12:g.37000971T>C
NG_007109.2:g.12622T>C
NM_000249.4:c.224T>CMANE SELECT
NM_001167617.3:c.-66T>C
NM_001167618.3:c.-500T>C
NM_001167619.3:c.-408T>C
NM_001258271.2:c.224T>C
NM_001258273.2:c.-500T>C
NM_001258274.3:c.-500T>C
NM_001354615.2:c.-403T>C
NM_001354616.2:c.-408T>C
NM_001354617.2:c.-500T>C
NM_001354618.2:c.-500T>C
NM_001354619.2:c.-500T>C
NM_001354620.2:c.-66T>C
NM_001354621.2:c.-593T>C
NM_001354622.2:c.-706T>C
NM_001354623.2:c.-706T>C
NM_001354624.2:c.-603T>C
NM_001354625.2:c.-506T>C
NM_001354626.2:c.-603T>C
NM_001354627.2:c.-603T>C
NM_001354628.2:c.224T>C
NM_001354629.2:c.208-3430T>C
NM_001354630.2:c.224T>C
NP_000240.1:p.Ile75Thr
NP_000240.1:p.Ile75Thr
NP_001245200.1:p.Ile75Thr
NP_001341557.1:p.Ile75Thr
NP_001341559.1:p.Ile75Thr
LRG_216t1:c.224T>C
LRG_216:g.12622T>C
LRG_216p1:p.Ile75Thr
NC_000003.11:g.37042462T>C
NM_000249.3:c.224T>C

Protein change:

I75T

Links:

dbSNP: rs876660839

NCBI 1000 Genomes Browser:

rs876660839

Molecular consequence:

NM_001167617.3:c.-66T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-408T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-403T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-408T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-500T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-66T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-593T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-706T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-706T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-506T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-603T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3430T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.224T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.224T>C - 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
SCV000278584	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 23, 2015)	germline	clinical testing	Citation Link,
SCV000684807	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 18, 2018)	germline	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

SCV000278584

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 23, 2015)

germline

clinical testing

Citation Link,

SCV000684807

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 18, 2018)

germline

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	clinical testing

Citations

PubMed

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 Ambry Genetics, SCV000278584.7

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

Description

The p.I75T variant (also known as c.224T>C), located in coding exon 3 of the MLH1 gene, results from a T to C substitution at nucleotide position 224. The isoleucine at codon 75 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of p.I75T remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000684807.2

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

#	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: Sep 29, 2024

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