NM_000249.4(MLH1):c.187G>A (p.Asp63Asn) AND Lynch syndrome

Clinical significance:Likely pathogenic (Last evaluated: Feb 26, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000075399.5

Allele description [Variation Report for NM_000249.4(MLH1):c.187G>A (p.Asp63Asn)]

NM_000249.4(MLH1):c.187G>A (p.Asp63Asn)

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.187G>A (p.Asp63Asn)
Other names:
p.D63N:GAC>AAC
HGVS:
  • NC_000003.12:g.36996689G>A
  • NG_007109.2:g.8340G>A
  • NG_008418.1:g.1616C>T
  • NM_000249.3:c.187G>A
  • NM_000249.4:c.187G>AMANE SELECT
  • NM_001167617.3:c.-103G>A
  • NM_001167618.3:c.-537G>A
  • NM_001167619.3:c.-445G>A
  • NM_001258271.2:c.187G>A
  • NM_001258273.1:c.-517+3026G>A
  • NM_001258273.2:c.-517+3026G>A
  • NM_001258274.3:c.-682G>A
  • NM_001354615.2:c.-440G>A
  • NM_001354616.2:c.-445G>A
  • NM_001354617.2:c.-537G>A
  • NM_001354618.2:c.-537G>A
  • NM_001354619.2:c.-537G>A
  • NM_001354620.2:c.-103G>A
  • NM_001354621.2:c.-630G>A
  • NM_001354622.2:c.-743G>A
  • NM_001354623.2:c.-723+2799G>A
  • NM_001354624.2:c.-640G>A
  • NM_001354625.2:c.-543G>A
  • NM_001354626.2:c.-640G>A
  • NM_001354627.2:c.-640G>A
  • NM_001354628.2:c.187G>A
  • NM_001354629.2:c.187G>A
  • NM_001354630.2:c.187G>A
  • NP_000240.1:p.Asp63Asn
  • NP_000240.1:p.Asp63Asn
  • NP_001245200.1:p.Asp63Asn
  • NP_001341557.1:p.Asp63Asn
  • NP_001341558.1:p.Asp63Asn
  • NP_001341559.1:p.Asp63Asn
  • LRG_216t1:c.187G>A
  • LRG_216:g.8340G>A
  • LRG_216p1:p.Asp63Asn
  • NC_000003.11:g.37038180G>A
  • p.D63N
Protein change:
D63N
Links:
dbSNP: rs63750850
NCBI 1000 Genomes Browser:
rs63750850
Molecular consequence:
  • NM_001167617.3:c.-103G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-537G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-445G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-682G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-440G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-445G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-537G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-537G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-537G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-103G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-630G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-743G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-640G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-543G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-640G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-640G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.1:c.-517+3026G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258273.2:c.-517+3026G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-723+2799G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.3:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000249.4:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Lynch syndrome
Synonyms:
Familial nonpolyposis colon cancer
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696133Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Feb 26, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha.

Räschle M, Dufner P, Marra G, Jiricny J.

J Biol Chem. 2002 Jun 14;277(24):21810-20. Epub 2002 Apr 10.

PubMed [citation]
PMID:
11948175

Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization.

van der Velde KJ, Kuiper J, Thompson BA, Plazzer JP, van Valkenhoef G, de Haan M, Jongbloed JD, Wijmenga C, de Koning TJ, Abbott KM, Sinke R, Spurdle AB, Macrae F, Genuardi M, Sijmons RH, Swertz MA; InSiGHT Group..

Hum Mutat. 2015 Jul;36(7):712-9. doi: 10.1002/humu.22798. Epub 2015 May 20.

PubMed [citation]
PMID:
25871441
PMCID:
PMC4973827
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696133.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: MLH1 c.187G>A (p.Asp63Asn) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246206 control chromosomes. c.187G>A has been reported in the literature in individuals affected with Lynch Syndrome (Papp_2007, Espenschied_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in dramatically reduced expression of both MLH1 and PMS2 proteins and reduced ATP'ase activity (Raschle_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Oct 25, 2021

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