NM_000179.3(MSH6):c.364G>A (p.Glu122Lys) AND not specified

Clinical significance:Likely benign (Last evaluated: Feb 16, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000780470.1

Allele description [Variation Report for NM_000179.3(MSH6):c.364G>A (p.Glu122Lys)]

NM_000179.3(MSH6):c.364G>A (p.Glu122Lys)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.364G>A (p.Glu122Lys)
Other names:
p.E122K:GAG>AAG
HGVS:
  • NC_000002.12:g.47791030G>A
  • NG_007111.1:g.12884G>A
  • NM_000179.2:c.364G>A
  • NM_000179.3:c.364G>AMANE SELECT
  • NM_001281492.2:c.237+7560G>A
  • NM_001281493.2:c.-373G>A
  • NM_001281494.2:c.-539G>A
  • NP_000170.1:p.Glu122Lys
  • NP_000170.1:p.Glu122Lys
  • LRG_219t1:c.364G>A
  • LRG_219:g.12884G>A
  • LRG_219p1:p.Glu122Lys
  • NC_000002.11:g.48018169G>A
  • p.E122K
Protein change:
E122K
Links:
dbSNP: rs143036974
NCBI 1000 Genomes Browser:
rs143036974
Molecular consequence:
  • NM_001281493.2:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281494.2:c.-539G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281492.2:c.237+7560G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000179.2:c.364G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.364G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000917743Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Feb 16, 2018)
germlineclinical testing

PubMed (2)
[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

Lysinuric Protein Intolerance Presenting with Multiple Fractures.

Posey JE, Burrage LC, Miller MJ, Liu P, Hardison MT, Elsea SH, Sun Q, Yang Y, Willis AS, Schlesinger AE, Bacino CA, Lee BH.

Mol Genet Metab Rep. 2014;1:176-183.

PubMed [citation]
PMID:
25419514
PMCID:
PMC4235665

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]
PMID:
23621914
PMCID:
PMC3651391

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917743.1

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

Description

Variant summary: MSH6 c.364G>A (p.Glu122Lys) results in a conservative amino acid change located in the PWWP domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting the variant is a benign polymorphism found primarily in populations of Latino origin. The c.364G>A variant has been reported in two publications without strong evidence for pathogenicity; thus, these reports do not provide unequivocal conclusions about an association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All of these laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Nov 27, 2021

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