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NM_000249.4(MLH1):c.133A>T (p.Thr45Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 19, 2015
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:
RCV000220580.3

Allele description [Variation Report for NM_000249.4(MLH1):c.133A>T (p.Thr45Ser)]

NM_000249.4(MLH1):c.133A>T (p.Thr45Ser)

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.133A>T (p.Thr45Ser)
HGVS:
  • NC_000003.12:g.36996635A>T
  • NG_007109.2:g.8286A>T
  • NG_008418.1:g.1670T>A
  • NM_000249.4:c.133A>TMANE SELECT
  • NM_001167617.3:c.-157A>T
  • NM_001167618.3:c.-591A>T
  • NM_001167619.3:c.-499A>T
  • NM_001258271.2:c.133A>T
  • NM_001258273.2:c.-517+2972A>T
  • NM_001258274.3:c.-736A>T
  • NM_001354615.2:c.-494A>T
  • NM_001354616.2:c.-499A>T
  • NM_001354617.2:c.-591A>T
  • NM_001354618.2:c.-591A>T
  • NM_001354619.2:c.-591A>T
  • NM_001354620.2:c.-157A>T
  • NM_001354621.2:c.-684A>T
  • NM_001354622.2:c.-797A>T
  • NM_001354623.2:c.-723+2745A>T
  • NM_001354624.2:c.-694A>T
  • NM_001354625.2:c.-597A>T
  • NM_001354626.2:c.-694A>T
  • NM_001354627.2:c.-694A>T
  • NM_001354628.2:c.133A>T
  • NM_001354629.2:c.133A>T
  • NM_001354630.2:c.133A>T
  • NP_000240.1:p.Thr45Ser
  • NP_000240.1:p.Thr45Ser
  • NP_001245200.1:p.Thr45Ser
  • NP_001341557.1:p.Thr45Ser
  • NP_001341558.1:p.Thr45Ser
  • NP_001341559.1:p.Thr45Ser
  • LRG_216t1:c.133A>T
  • LRG_216:g.8286A>T
  • LRG_216p1:p.Thr45Ser
  • NC_000003.11:g.37038126A>T
  • NM_000249.3:c.133A>T
Protein change:
T45S
Links:
dbSNP: rs876658416
NCBI 1000 Genomes Browser:
rs876658416
Molecular consequence:
  • NM_001167617.3:c.-157A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-591A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-499A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-736A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-494A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-499A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-591A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-591A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-591A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-157A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-684A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-797A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-694A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-597A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-694A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-694A>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-517+2972A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-723+2745A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.133A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.133A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.133A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.133A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.133A>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000273597Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Jan 19, 2015) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Details of each submission

From Ambry Genetics, SCV000273597.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.T45S variant (also known as c.133A>T), located in coding exon 2 of the MLH1 gene, results from an A to T substitution at nucleotide position 133. The threonine at codon 45 is replaced by serine, an amino acid with similar properties. While this exact variant has not been reported in the literature, an alteration at the same codon, p.Thr45Ile (c.134C>T), was assessed in an in vivo hybrid yeast-human MLH1 assay and was found to have >67% reduced MMR activity (Ellison AR et al, Nucleic Acids Res. 2004 ; 32(18):5321-38). The p.T45S 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 42,000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign 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.T45S remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024