NM_000179.3(MSH6):c.1144C>T (p.His382Tyr) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000627690.5

Allele description [Variation Report for NM_000179.3(MSH6):c.1144C>T (p.His382Tyr)]

NM_000179.3(MSH6):c.1144C>T (p.His382Tyr)

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.1144C>T (p.His382Tyr)
HGVS:
  • NC_000002.12:g.47799127C>T
  • NG_007111.1:g.20981C>T
  • NM_000179.2:c.1144C>T
  • NM_000179.3:c.1144C>TMANE SELECT
  • NM_001281492.2:c.754C>T
  • NM_001281493.2:c.238C>T
  • NM_001281494.2:c.238C>T
  • NP_000170.1:p.His382Tyr
  • NP_000170.1:p.His382Tyr
  • NP_001268421.1:p.His252Tyr
  • NP_001268422.1:p.His80Tyr
  • NP_001268423.1:p.His80Tyr
  • LRG_219t1:c.1144C>T
  • LRG_219:g.20981C>T
  • LRG_219p1:p.His382Tyr
  • NC_000002.11:g.48026266C>T
  • p.H382Y
Protein change:
H252Y
Links:
dbSNP: rs587779207
NCBI 1000 Genomes Browser:
rs587779207
Molecular consequence:
  • NM_000179.2:c.1144C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1144C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.754C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.238C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.238C>T - 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
SCV000551091Invitaecriteria provided, single submitter
Uncertain significance
(Oct 21, 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

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]
PMID:
26689913
PMCID:
PMC4703835

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]
PMID:
21520333
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000551091.7

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

Description

This sequence change replaces histidine with tyrosine at codon 382 of the MSH6 protein (p.His382Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs587779207, ExAC <0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 26689913). It has also been reported in an individual affected with colon cancer in the Leiden Open-source Variation Database (PMID: 21520333). However, in that individual, a pathogenic allele was also identified in the MSH2 gene, which suggests that this c.1144C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89176). 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: 26333163), suggest that this missense change is likely to be tolerated. These predictions have not been confirmed by published functional studies and their 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: Oct 30, 2021

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