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NM_000179.2(MSH6):c.2291C>A (p.Thr764Asn) AND Hereditary nonpolyposis colon cancer

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 29, 2017
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000630065.1

Allele description

NM_000179.2(MSH6):c.2291C>A (p.Thr764Asn)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.2291C>A (p.Thr764Asn)
HGVS:
  • NC_000002.12:g.47800274C>A
  • NG_007111.1:g.22128C>A
  • NM_000179.2:c.2291C>A
  • NP_000170.1:p.Thr764Asn
  • LRG_219t1:c.2291C>A
  • LRG_219:g.22128C>A
  • LRG_219p1:p.Thr764Asn
  • NC_000002.11:g.48027413C>A
  • p.T764N
Protein change:
T764N
Links:
dbSNP: rs561198849
GMAF:
0.0002(T), 561198849
NCBI 1000 Genomes Browser:
rs561198849
Allele Frequency:
0.00001(A)
Molecular consequence:
  • NM_000179.2:c.2291C>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
SCV000751021Invitae
criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))
Uncertain significance
(Dec 29, 2017)
germlineclinical testing

PubMed (3)
[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(1):25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]
PMID:
23621914
PMCID:
PMC3651391

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry.

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]
PMID:
15713769
PMCID:
PMC2933041
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000751021.1

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

Description

This sequence change replaces threonine with asparagine at codon 764 of the MSH6 protein (p.Thr764Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs561198849, ExAC 0.006%). This variant has been observed in an individua with Lynch syndrome (PMID: 15713769). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2291C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 184444). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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