NM_000249.4(MLH1):c.1034C>T (p.Thr345Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 30, 2021
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:: RCV000565439.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1034C>T (p.Thr345Ile)]

NM_000249.4(MLH1):c.1034C>T (p.Thr345Ile)

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.1034C>T (p.Thr345Ile)

HGVS:

NC_000003.12:g.37020459C>T
NG_007109.2:g.32110C>T
NM_000249.4:c.1034C>TMANE SELECT
NM_001167617.3:c.740C>T
NM_001167618.3:c.311C>T
NM_001167619.3:c.311C>T
NM_001258271.2:c.1034C>T
NM_001258273.2:c.311C>T
NM_001258274.3:c.311C>T
NM_001354615.2:c.311C>T
NM_001354616.2:c.311C>T
NM_001354617.2:c.311C>T
NM_001354618.2:c.311C>T
NM_001354619.2:c.311C>T
NM_001354620.2:c.740C>T
NM_001354621.2:c.11C>T
NM_001354622.2:c.11C>T
NM_001354623.2:c.11C>T
NM_001354624.2:c.-36-5178C>T
NM_001354625.2:c.-36-5178C>T
NM_001354626.2:c.-36-5178C>T
NM_001354627.2:c.-36-5178C>T
NM_001354628.2:c.1034C>T
NM_001354629.2:c.935C>T
NM_001354630.2:c.1034C>T
NP_000240.1:p.Thr345Ile
NP_000240.1:p.Thr345Ile
NP_001161089.1:p.Thr247Ile
NP_001161090.1:p.Thr104Ile
NP_001161091.1:p.Thr104Ile
NP_001245200.1:p.Thr345Ile
NP_001245202.1:p.Thr104Ile
NP_001245203.1:p.Thr104Ile
NP_001341544.1:p.Thr104Ile
NP_001341545.1:p.Thr104Ile
NP_001341546.1:p.Thr104Ile
NP_001341547.1:p.Thr104Ile
NP_001341548.1:p.Thr104Ile
NP_001341549.1:p.Thr247Ile
NP_001341550.1:p.Thr4Ile
NP_001341551.1:p.Thr4Ile
NP_001341552.1:p.Thr4Ile
NP_001341557.1:p.Thr345Ile
NP_001341558.1:p.Thr312Ile
NP_001341559.1:p.Thr345Ile
LRG_216t1:c.1034C>T
LRG_216:g.32110C>T
LRG_216p1:p.Thr345Ile
NC_000003.11:g.37061950C>T
NM_000249.3:c.1034C>T

Protein change:

T104I

Links:

dbSNP: rs750980386

NCBI 1000 Genomes Browser:

rs750980386

Molecular consequence:

NM_001354624.2:c.-36-5178C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-36-5178C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-36-5178C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-36-5178C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1034C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.740C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1034C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.311C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.740C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.11C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1034C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.935C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1034C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000662019	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jul 30, 2021)	germline	clinical testing	Citation Link,
SCV001735155	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 8, 2020)	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

SCV000662019

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jul 30, 2021)

germline

clinical testing

Citation Link,

SCV001735155

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 8, 2020)

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	1	not provided	not provided	1	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, SCV000662019.4

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

Description

The p.T345I variant (also known as c.1034C>T), located in coding exon 11 of the MLH1 gene, results from a C to T substitution at nucleotide position 1034. The threonine at codon 345 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001735155.1

#	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 threonine with isoleucine at codon 345 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 hereditary cancer in the literature. This variant has been identified in 2/251072 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: Feb 28, 2024

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