NM_000249.4(MLH1):c.107T>C (p.Ile36Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 15, 2024
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:: RCV001009839.7

Allele description [Variation Report for NM_000249.4(MLH1):c.107T>C (p.Ile36Thr)]

NM_000249.4(MLH1):c.107T>C (p.Ile36Thr)

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.107T>C (p.Ile36Thr)

HGVS:

NC_000003.12:g.36993654T>C
NG_007109.2:g.5305T>C
NG_008418.1:g.4651A>G
NM_000249.4:c.107T>CMANE SELECT
NM_001167617.3:c.-410T>C
NM_001167618.3:c.-839T>C
NM_001167619.3:c.-752T>C
NM_001258271.2:c.107T>C
NM_001258273.2:c.-526T>C
NM_001258274.3:c.-989T>C
NM_001354615.2:c.-520T>C
NM_001354616.2:c.-520T>C
NM_001354617.2:c.-612T>C
NM_001354618.2:c.-844T>C
NM_001354619.2:c.-968T>C
NM_001354620.2:c.-178T>C
NM_001354621.2:c.-937T>C
NM_001354622.2:c.-1050T>C
NM_001354623.2:c.-959T>C
NM_001354624.2:c.-720T>C
NM_001354625.2:c.-618T>C
NM_001354626.2:c.-715T>C
NM_001354627.2:c.-947T>C
NM_001354628.2:c.107T>C
NM_001354629.2:c.107T>C
NM_001354630.2:c.107T>C
NP_000240.1:p.Ile36Thr
NP_000240.1:p.Ile36Thr
NP_001245200.1:p.Ile36Thr
NP_001341557.1:p.Ile36Thr
NP_001341558.1:p.Ile36Thr
NP_001341559.1:p.Ile36Thr
LRG_216t1:c.107T>C
LRG_216:g.5305T>C
LRG_216p1:p.Ile36Thr
NC_000003.11:g.37035145T>C
NM_000249.3:c.107T>C

Protein change:

I36T

Links:

dbSNP: rs267607707

NCBI 1000 Genomes Browser:

rs267607707

Molecular consequence:

NM_001167617.3:c.-410T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-839T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-752T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-526T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-989T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-520T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-520T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-612T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-844T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-968T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-178T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-937T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1050T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-959T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-720T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-618T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-715T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-947T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.107T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.107T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.107T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.107T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.107T>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
SCV001169955	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 15, 2024)	germline	clinical testing	Citation Link,
SCV001344986	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 8, 2023)	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

SCV001169955

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 15, 2024)

germline

clinical testing

Citation Link,

SCV001344986

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 8, 2023)

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, SCV001169955.5

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

Description

The p.I36T variant (also known as c.107T>C), located in coding exon 1 of the MLH1 gene, results from a T to C substitution at nucleotide position 107. The isoleucine at codon 36 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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, SCV001344986.2

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

Description

This missense variant replaces isoleucine with threonine at codon 36 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 not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/250752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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