NM_000249.3(MLH1):c.1007G>A (p.Gly336Asp) AND Hereditary nonpolyposis colon cancer

Clinical significance:Uncertain significance (Last evaluated: Nov 3, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000196459.5

Allele description

NM_000249.3(MLH1):c.1007G>A (p.Gly336Asp)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.3(MLH1):c.1007G>A (p.Gly336Asp)
HGVS:
  • NC_000003.12:g.37020432G>A
  • NM_000249.3:c.1007G>A
  • NM_001354624.1:c.-36-5205G>A
  • NP_000240.1:p.Gly336Asp
  • LRG_216t1:c.1007G>A
  • LRG_216:g.32083G>A
  • LRG_216p1:p.Gly336Asp
  • NC_000003.11:g.37061923G>A
  • p.G336D
Protein change:
G336D
Links:
dbSNP: rs587781750
NCBI 1000 Genomes Browser:
rs587781750
Allele Frequency:
0.00002(A)
Molecular consequence:
  • NM_001354624.1:c.-36-5205G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.3:c.1007G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colon cancer
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000254343Invitaecriteria provided, single submitter
Uncertain significance
(Nov 3, 2017)
germlineclinical testing

PubMed (2)
[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

UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families.

Grandval P, Fabre AJ, Gaildrat P, Baert-Desurmont S, Buisine MP, Ferrari A, Wang Q, Béroud C, Olschwang S.

Database (Oxford). 2013 May 31;2013:bat036. doi: 10.1093/database/bat036. Print 2013.

PubMed [citation]
PMID:
23729658
PMCID:
PMC3668602

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000254343.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glycine with aspartic acid at codon 336 of the MLH1 protein (p.Gly336Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs587781750, ExAC 0.003%). This variant has been reported in an individual in the Universal Mutation Database (UMD) (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 141442). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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: Jul 21, 2018

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