NM_000179.2(MSH6):c.2561_2562delinsTT (p.Lys854Ile) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Jul 15, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000214497.6

Allele description [Variation Report for NM_000179.2(MSH6):c.2561_2562delinsTT (p.Lys854Ile)]

NM_000179.2(MSH6):c.2561_2562delinsTT (p.Lys854Ile)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Indel
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.2(MSH6):c.2561_2562delinsTT (p.Lys854Ile)
HGVS:
  • NC_000002.12:g.47800544_47800545delinsTT
  • NG_007111.1:g.22398_22399delinsTT
  • NM_000179.2:c.2561_2562delinsTT
  • NM_001281492.1:c.2171_2172delinsTT
  • NM_001281493.1:c.1655_1656delinsTT
  • NM_001281494.1:c.1655_1656delinsTT
  • NP_000170.1:p.Lys854Ile
  • NP_001268421.1:p.Lys724Ile
  • NP_001268422.1:p.Lys552Ile
  • NP_001268423.1:p.Lys552Ile
  • LRG_219t1:c.2561_2562delinsTT
  • LRG_219:g.22398_22399delinsTT
  • LRG_219p1:p.Lys854Ile
  • NC_000002.11:g.48027683_48027684delAGinsTT
  • NC_000002.11:g.48027683_48027684delinsTT
  • NM_000179.2:c.2561_2562delAGinsTT
Protein change:
K552I
Links:
dbSNP: rs587780673
NCBI 1000 Genomes Browser:
rs587780673
Molecular consequence:
  • NM_000179.2:c.2561_2562delinsTT - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.2171_2172delinsTT - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.1655_1656delinsTT - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.1655_1656delinsTT - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000273126Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jul 15, 2020)
germlineclinical testing

Citation Link,

SCV000685295Color Health, Inccriteria provided, single submitter
Uncertain significance
(Oct 11, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Description

This missense variant replaces lysine with isoleucine at codon 854 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant is reported as two single nucleotide variants identified in 105/280696 chromosomes for chr2.GRCh37:g.48027683A>T and 22/280654 chromosomes for chr2.GRCh37:g.48027684G>T in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV000685295

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000273126.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.2561_2562delAGinsTT variant (also known as p.K854I), located in coding exon 4 of the MSH6 gene, results from an in-frame deletion of AG and insertion of TT at nucleotide positions 2561 to 2562. This results in the substitution of the lysine residue for an isoleucine residue at codon 854, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000685295.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 16, 2021

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