NM_000249.4(MLH1):c.218T>G (p.Leu73Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 23, 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:: RCV000213759.10

Allele description [Variation Report for NM_000249.4(MLH1):c.218T>G (p.Leu73Arg)]

NM_000249.4(MLH1):c.218T>G (p.Leu73Arg)

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.218T>G (p.Leu73Arg)

HGVS:

NC_000003.12:g.37000965T>G
NG_007109.2:g.12616T>G
NM_000249.4:c.218T>GMANE SELECT
NM_001167617.3:c.-72T>G
NM_001167618.3:c.-506T>G
NM_001167619.3:c.-414T>G
NM_001258271.2:c.218T>G
NM_001258273.2:c.-506T>G
NM_001258274.3:c.-506T>G
NM_001354615.2:c.-409T>G
NM_001354616.2:c.-414T>G
NM_001354617.2:c.-506T>G
NM_001354618.2:c.-506T>G
NM_001354619.2:c.-506T>G
NM_001354620.2:c.-72T>G
NM_001354621.2:c.-599T>G
NM_001354622.2:c.-712T>G
NM_001354623.2:c.-712T>G
NM_001354624.2:c.-609T>G
NM_001354625.2:c.-512T>G
NM_001354626.2:c.-609T>G
NM_001354627.2:c.-609T>G
NM_001354628.2:c.218T>G
NM_001354629.2:c.208-3436T>G
NM_001354630.2:c.218T>G
NP_000240.1:p.Leu73Arg
NP_000240.1:p.Leu73Arg
NP_001245200.1:p.Leu73Arg
NP_001341557.1:p.Leu73Arg
NP_001341559.1:p.Leu73Arg
LRG_216t1:c.218T>G
LRG_216:g.12616T>G
LRG_216p1:p.Leu73Arg
NC_000003.11:g.37042456T>G
NM_000249.3:c.218T>G

Protein change:

L73R; LEU73ARG

Links:

OMIM: 120436.0034; dbSNP: rs397514684

NCBI 1000 Genomes Browser:

rs397514684

Molecular consequence:

NM_001167617.3:c.-72T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-414T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-409T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-414T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-506T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-72T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-599T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-712T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-712T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-609T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-512T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-609T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-609T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354629.2:c.208-3436T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.218T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.218T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.218T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.218T>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
SCV000274574	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 23, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274574

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 23, 2015)

germline

clinical testing

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

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

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome.

Baas AF, Gabbett M, Rimac M, Kansikas M, Raphael M, Nievelstein RA, Nicholls W, Offerhaus J, Bodmer D, Wernstedt A, Krabichler B, Strasser U, Nyström M, Zschocke J, Robertson SP, van Haelst MM, Wimmer K.

Eur J Hum Genet. 2013 Jan;21(1):55-61. doi: 10.1038/ejhg.2012.117. Epub 2012 Jun 13.

PubMed [citation]

PMID:: 22692065
PMCID:: PMC3522206

Details of each submission

From Ambry Genetics, SCV000274574.7

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

Description

The p.L73R variant (also known as c.218T>G), located in coding exon 3 of the MLH1 gene, results from a T to G substitution at nucleotide position 218. The leucine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a homozygous state in a male of Polynesian ancestry whose clinical history was consistent with constitutional mismatch repair deficiency (CMMR-D) . This individual developed glioblastoma multiforme (3 years) and T-cell lymphoblastic lymphoma (5.5 years); he was also noted to have near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia and multiple cafe-au-lait spots. The maternal family history was also positive for colorectal cancer (Baas AF et al. Eur. J. Hum. Genet. 2013 Jan; 21(1):55-61). This amino acid position is well conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). 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: Oct 26, 2024

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