NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000230963.8

Allele description [Variation Report for NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu)]

NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu)

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.1746T>G (p.Phe582Leu)
Other names:
p.F582L:TTT>TTG
HGVS:
  • NC_000002.12:g.47799729T>G
  • NG_007111.1:g.21583T>G
  • NM_000179.3:c.1746T>GMANE SELECT
  • NM_001281492.2:c.1356T>G
  • NM_001281493.2:c.840T>G
  • NM_001281494.2:c.840T>G
  • NP_000170.1:p.Phe582Leu
  • NP_000170.1:p.Phe582Leu
  • NP_001268421.1:p.Phe452Leu
  • NP_001268422.1:p.Phe280Leu
  • NP_001268423.1:p.Phe280Leu
  • LRG_219t1:c.1746T>G
  • LRG_219:g.21583T>G
  • LRG_219p1:p.Phe582Leu
  • NC_000002.11:g.48026868T>G
  • NM_000179.2:c.1746T>G
  • p.F582L
Protein change:
F280L
Links:
dbSNP: rs201518545
NCBI 1000 Genomes Browser:
rs201518545
Molecular consequence:
  • NM_000179.3:c.1746T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.1356T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.840T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.840T>G - 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
SCV000283726Invitaecriteria provided, single submitter
Uncertain significance
(Oct 12, 2020)
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

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

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, SCV000283726.8

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

Description

This sequence change replaces phenylalanine with leucine at codon 582 of the MSH6 protein (p.Phe582Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs201518545, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127563). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. In addition, the leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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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