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NM_000249.4(MLH1):c.306G>T (p.Glu102Asp) AND Hereditary nonpolyposis colon cancer

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 22, 2022
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:
RCV002228180.1

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]

Condition(s)

Name:
Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:
Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:
MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002511439Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 22, 2022) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C.

Cancer Res. 2007 May 15;67(10):4595-604.

PubMed [citation]
PMID:
17510385

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).

Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM.

Hum Mutat. 2008 Jun;29(6):852-60. doi: 10.1002/humu.20735.

PubMed [citation]
PMID:
18383312
See all PubMed Citations (12)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

Variant summary: MLH1 c.306G>T (p.Glu102Asp) results in a conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the last nucleotide of exon 3, therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, while three predict the variant weakens/abolishes a cryptic 5' donor site, which is located 5 nucleotides upstream from the canonical splice site. One observation from a patient carrying c.303T>G and c.306G>T in trans showed that allele c.306G>T did not produce any wild-type splice product, strongly suggesting for a pathogenic outcome by defective splicing (poster from Myriad Genetics, 2015 ASHG meeting). A different variant affecting the same nucleotide (i.e. a G>C change) was found to cause a splicing defect (Borras_2012). The variant allele was found at a frequency of 1.2e-05 in 251464 control chromosomes (gnomAD). c.306G>T has been reported in the literature in several individuals affected with Lynch Syndrome associated tumors (e.g. Chao_2008, Kovac_2011, Susswein_2016, Whitworth_2016, Sethi_2016, Kim_2020, Nagabhushana_2021), and in multiple cases loss of MLH1 and PMS2 expression and / or high microsatellite instability was described in the associated tumor, although in a few cases retained MMR protein expression was also noted. These data indicate that the variant is likely to be associated with disease. An in vitro study, examining the protein level effects of this missense change demonstrated that the variant resulted in retained protein expression (>75% of wild-type) with a somewhat reduced MMR activity (<60% of wild-type; Takahashi_2007), however, authors used an intronless cDNA sequence for mutagenesis, and in light of the (potential) spliceogenic effect, these findings might not reflect the overall in vivo consequences of the variant. Eight submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=4) / likely pathogenic (n=3), while the expert panel called the variant as VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024