NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000656835.12

Allele description [Variation Report for NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile)]

NM_007194.4(CHEK2):c.1133C>T (p.Thr378Ile)

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.1133C>T (p.Thr378Ile)

Other names:

p.T378I:ACC>ATC

HGVS:

NC_000022.11:g.28695836G>A
NG_008150.2:g.51031C>T
NM_001005735.2:c.1262C>T
NM_001257387.2:c.470C>T
NM_001349956.2:c.932C>T
NM_007194.4:c.1133C>TMANE SELECT
NM_145862.2:c.1046C>T
NP_001005735.1:p.Thr421Ile
NP_001244316.1:p.Thr157Ile
NP_001336885.1:p.Thr311Ile
NP_009125.1:p.Thr378Ile
NP_665861.1:p.Thr349Ile
LRG_302t1:c.1133C>T
LRG_302:g.51031C>T
LRG_302p1:p.Thr378Ile
NC_000022.10:g.29091824G>A
NG_008150.1:g.50999C>T
NM_007194.3:c.1133C>T
p.T378I

Protein change:

T157I

Links:

dbSNP: rs587780167

NCBI 1000 Genomes Browser:

rs587780167

Molecular consequence:

NM_001005735.2:c.1262C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257387.2:c.470C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.932C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.1133C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.1046C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149893	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 11, 2024)	germline	clinical testing	Citation Link,
SCV000601144	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Oct 4, 2022)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31206626, 33471991, 30851065, 26467025
SCV005197498	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 12, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149893

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 11, 2024)

germline

clinical testing

Citation Link,

SCV000601144

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Oct 4, 2022)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005197498

Clinical Genetics Laboratory, Skane University Hospital Lund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 12, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

Weitzel JN, Neuhausen SL, Adamson A, Tao S, Ricker C, Maoz A, Rosenblatt M, Nehoray B, Sand S, Steele L, Unzeitig G, Feldman N, Blanco AM, Hu D, Huntsman S, Castillo D, Haiman C, Slavin T, Ziv E.

Cancer. 2019 Aug 15;125(16):2829-2836. doi: 10.1002/cncr.32083. Epub 2019 Jun 17.

PubMed [citation]

PMID:: 31206626
PMCID:: PMC7376605

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000149893.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate DNA damage response and cell growth comparable to wild type in yeast-based assays but impaired kinase activity and auto-phosphorylation in human-cell based studies (PMID: 30851065, 37449874); Observed in individuals with breast cancer and in unaffected controls (PMID: 31206626, 33471991, 34282249, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33471991, 30851065, 31206626, 34282249, 37449874, 22419737, 19782031, 20713355, 17698850)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601144.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The frequency of this variant in the general population, 0.00012 (4/34568 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in individuals affected with breast cancer and unaffected controls (PMIDs: 30851065 (2019) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast-based functional study has indicated that this variant maintains CHEK2 protein function (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197498.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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