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NM_000249.4(MLH1):c.306G>T (p.Glu102Asp) AND Carcinoma of colon

Germline classification:
Pathogenic (1 submission)
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV001353746.1

Allele description [Variation Report for NM_000249.4(MLH1):c.306G>T (p.Glu102Asp)]

NM_000249.4(MLH1):c.306G>T (p.Glu102Asp)

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.306G>T (p.Glu102Asp)
Other names:
p.E102D:GAG>GAT
HGVS:
  • NC_000003.12:g.37001053G>T
  • NG_007109.2:g.12704G>T
  • NM_000249.4:c.306G>TMANE SELECT
  • NM_001167617.3:c.12+5G>T
  • NM_001167618.3:c.-418G>T
  • NM_001167619.3:c.-326G>T
  • NM_001258271.2:c.306G>T
  • NM_001258273.2:c.-418G>T
  • NM_001258274.3:c.-418G>T
  • NM_001354615.2:c.-326+5G>T
  • NM_001354616.2:c.-326G>T
  • NM_001354617.2:c.-418G>T
  • NM_001354618.2:c.-418G>T
  • NM_001354619.2:c.-418G>T
  • NM_001354620.2:c.12+5G>T
  • NM_001354621.2:c.-511G>T
  • NM_001354622.2:c.-624G>T
  • NM_001354623.2:c.-624G>T
  • NM_001354624.2:c.-521G>T
  • NM_001354625.2:c.-429+5G>T
  • NM_001354626.2:c.-521G>T
  • NM_001354627.2:c.-521G>T
  • NM_001354628.2:c.306G>T
  • NM_001354629.2:c.208-3348G>T
  • NM_001354630.2:c.306G>T
  • NP_000240.1:p.Glu102Asp
  • NP_000240.1:p.Glu102Asp
  • NP_001245200.1:p.Glu102Asp
  • NP_001341557.1:p.Glu102Asp
  • NP_001341559.1:p.Glu102Asp
  • LRG_216t1:c.306G>T
  • LRG_216:g.12704G>T
  • LRG_216p1:p.Glu102Asp
  • NC_000003.11:g.37042544G>T
  • NM_000249.3:c.306G>T
Protein change:
E102D
Links:
dbSNP: rs63751665
NCBI 1000 Genomes Browser:
rs63751665
Molecular consequence:
  • NM_001167618.3:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-326G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-326G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-418G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-511G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-624G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-624G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-521G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-521G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-521G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167617.3:c.12+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.-326+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354620.2:c.12+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-429+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354629.2:c.208-3348G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.306G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.306G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.306G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.306G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
effect on RNA splicing [Variation Ontology: 0362]
Observations:
10

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000592349Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes10not providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592349.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testingnot provided

Description

The p.Glu102Asp variant has been previously reported in the literature and by our laboratory. Takahashi (2007) reported this variant in 1/202 proband chromosomes; however, the proband in this case was not informative for HNPCC. In-vitro mismatch repair analysis demonstrated that the p.Glu102Asp variant had 56.1% activity and >75% relative MLH1 expression (Takahashi 2007). In addition, this variant has previously been reported by our laboratory in one family where segregation of this variant was observed with Lynch related cancers in 3 individuals and both MLH1 deficiency and MSI tumours were demonstrated in more than one case, increasing the likelihood that this variant is pathogenic. In addition, the p.Glu102 residue is conserved across mammals, lower species and computational analyses (PolyPhen-2, MAPP, AlignGVGD) suggest that the p.Glu102Asp variant may impact the protein. The p.Glu102Asp (c.306G>T) variant occurs in the last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 4 of 4 different programs, increasing the likelihood this variant may have clinical significance. However, this in-silico and conservation information is not predictive enough to assume pathogenicity. Another variant at the same amino acid residue, p.Glu102Lys, has been identified in 1/42 proband chromosomes from the Creighton University Hereditary Cancer Institute in individuals whom satisfied the Bethesda criteria (Chao 2008). An additional study identified the p.Glu102Lys variant in 1/8 proband chromosomes (who met Amsterdam criteria) and demonstrated that the nucleotide change abrogated the splicing pattern of exon 3, resulting in a 5-bp deletion in the transcript (Nagawa 2002). Furthermore, the p.Glu102Lys variant was demonstrated to be a loss of function variant by in-vitro complementation analysis (Ellison 2001). In summary, based on the above information, this variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided10not providednot providednot provided

Last Updated: Sep 29, 2024