NM_000249.4(MLH1):c.595G>C (p.Glu199Gln) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000627702.4

Allele description [Variation Report for NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)]

NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)

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.595G>C (p.Glu199Gln)
HGVS:
  • NC_000003.12:g.37012017G>C
  • NG_007109.2:g.23668G>C
  • NM_000249.4:c.595G>CMANE SELECT
  • NM_001167617.3:c.301G>C
  • NM_001167618.3:c.-129G>C
  • NM_001167619.3:c.-129G>C
  • NM_001258271.2:c.595G>C
  • NM_001258273.2:c.-129G>C
  • NM_001258274.3:c.-129G>C
  • NM_001354615.2:c.-129G>C
  • NM_001354616.2:c.-129G>C
  • NM_001354617.2:c.-129G>C
  • NM_001354618.2:c.-129G>C
  • NM_001354619.2:c.-129G>C
  • NM_001354620.2:c.301G>C
  • NM_001354621.2:c.-222G>C
  • NM_001354622.2:c.-335G>C
  • NM_001354623.2:c.-335G>C
  • NM_001354624.2:c.-232G>C
  • NM_001354625.2:c.-232G>C
  • NM_001354626.2:c.-232G>C
  • NM_001354627.2:c.-232G>C
  • NM_001354628.2:c.595G>C
  • NM_001354629.2:c.496G>C
  • NM_001354630.2:c.595G>C
  • NP_000240.1:p.Glu199Gln
  • NP_000240.1:p.Glu199Gln
  • NP_001161089.1:p.Glu101Gln
  • NP_001245200.1:p.Glu199Gln
  • NP_001341549.1:p.Glu101Gln
  • NP_001341557.1:p.Glu199Gln
  • NP_001341558.1:p.Glu166Gln
  • NP_001341559.1:p.Glu199Gln
  • LRG_216t1:c.595G>C
  • LRG_216:g.23668G>C
  • LRG_216p1:p.Glu199Gln
  • NC_000003.11:g.37053508G>C
  • NM_000249.3:c.595G>C
  • p.E199Q
Protein change:
E101Q
Links:
dbSNP: rs63749887
NCBI 1000 Genomes Browser:
rs63749887
Molecular consequence:
  • NM_001167618.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-129G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-222G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-335G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-232G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.301G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.301G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.496G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.595G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000543610Invitaecriteria provided, single submitter
Uncertain significance
(Oct 28, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1.

Wahlberg S, Liu T, Lindblom P, Lindblom A.

Genet Test. 1999;3(3):259-64.

PubMed [citation]
PMID:
10495924
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000543610.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glutamic acid with glutamine at codon 199 of the MLH1 protein (p.Glu199Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs63749887, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a healthy control individual with no family history of colorectal cancer (PMID: 10495924). ClinVar contains an entry for this variant (Variation ID: 90293). An experimental study has shown that this variant does not affect MLH1 mismatch repair activity or protein expression in vitro (PMID: 17510385) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Dec 4, 2021

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