NM_007194.4(CHEK2):c.1078G>A (p.Glu360Lys) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Sep 10, 2019)

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:
RCV000220180.5

Allele description [Variation Report for NM_007194.4(CHEK2):c.1078G>A (p.Glu360Lys)]

NM_007194.4(CHEK2):c.1078G>A (p.Glu360Lys)

Gene:
CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q12.1
Genomic location:
Preferred name:
NM_007194.4(CHEK2):c.1078G>A (p.Glu360Lys)
HGVS:
  • NC_000022.11:g.28696918C>T
  • NG_008150.1:g.49917G>A
  • NG_008150.2:g.49949G>A
  • NM_001005735.2:c.1207G>A
  • NM_001257387.2:c.415G>A
  • NM_001349956.2:c.877G>A
  • NM_007194.4:c.1078G>AMANE SELECT
  • NM_145862.2:c.1009-1045G>A
  • NP_001005735.1:p.Glu403Lys
  • NP_001244316.1:p.Glu139Lys
  • NP_001336885.1:p.Glu293Lys
  • NP_009125.1:p.Glu360Lys
  • LRG_302t1:c.1078G>A
  • LRG_302:g.49949G>A
  • LRG_302p1:p.Glu360Lys
  • NC_000022.10:g.29092906C>T
  • NM_007194.3:c.1078G>A
Protein change:
E139K
Links:
dbSNP: rs876658337
NCBI 1000 Genomes Browser:
rs876658337
Molecular consequence:
  • NM_145862.2:c.1009-1045G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001005735.2:c.1207G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257387.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349956.2:c.877G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007194.4:c.1078G>A - 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
SCV000273428Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jun 14, 2018)
germlineclinical testing

Citation Link,

SCV000684556Color Health, Inccriteria provided, single submitter
Uncertain significance
(Sep 10, 2019)
germlineclinical testing

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

Description

This missense variant replaces glutamic acid with lysine at codon 360 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). 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 has not been identified 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.

SCV000684556

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, SCV000273428.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.E360K variant (also known as c.1078G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1078. The glutamic acid at codon 360 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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, SCV000684556.3

#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: Nov 27, 2021

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