NM_007194.4(CHEK2):c.134C>T (p.Thr45Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 13, 2022
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:: RCV000214565.14

Allele description [Variation Report for NM_007194.4(CHEK2):c.134C>T (p.Thr45Met)]

NM_007194.4(CHEK2):c.134C>T (p.Thr45Met)

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.134C>T (p.Thr45Met)

HGVS:

NC_000022.11:g.28734588G>A
NG_008150.2:g.12279C>T
NM_001005735.2:c.134C>T
NM_001257387.2:c.-644C>T
NM_001349956.2:c.134C>T
NM_007194.4:c.134C>TMANE SELECT
NM_145862.2:c.134C>T
NP_001005735.1:p.Thr45Met
NP_001336885.1:p.Thr45Met
NP_009125.1:p.Thr45Met
NP_665861.1:p.Thr45Met
LRG_302t1:c.134C>T
LRG_302:g.12279C>T
LRG_302p1:p.Thr45Met
NC_000022.10:g.29130576G>A
NG_008150.1:g.12247C>T
NM_007194.3:c.134C>T

Protein change:

T45M

Links:

dbSNP: rs558321010

NCBI 1000 Genomes Browser:

rs558321010

Molecular consequence:

NM_001257387.2:c.-644C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274148	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32546565, 32832836, 33471991 Citation Link,
SCV000903493	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26580448, 27498913, 28944238, 25741868
SCV002537051	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Mar 21, 2022)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26580448, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274148

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000903493

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 13, 2022)

germline

clinical testing

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

SCV002537051

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Mar 21, 2022)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

Song H, Dicks EM, Tyrer J, Intermaggio M, Chenevix-Trench G, Bowtell DD, Traficante N, Group A, Brenton J, Goranova T, Hosking K, Piskorz A, van Oudenhove E, Doherty J, Harris HR, Rossing MA, Duerst M, Dork T, Bogdanova NV, Modugno F, Moysich K, Odunsi K, et al.

J Med Genet. 2021 May;58(5):305-313. doi: 10.1136/jmedgenet-2019-106739. Epub 2020 Jun 16.

PubMed [citation]

PMID:: 32546565
PMCID:: PMC8086250

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

Matejcic M, Patel Y, Lilyquist J, Hu C, Lee KY, Gnanaolivu RD, Hart SN, Polley EC, Yadav S, Boddicker NJ, Samara R, Xia L, Sheng X, Lubmawa A, Kiddu V, Masaba B, Namuguzi D, Mutema G, Job K, Henry DM, Ingles SA, Wilkens L, et al.

JCO Precis Oncol. 2020;4:32-43. doi: 10.1200/po.19.00179. Epub 2020 Jan 31.

PubMed [citation]

PMID:: 32832836
PMCID:: PMC7442213

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000274148.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.T45M variant (also known as c.134C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 134. The threonine at codon 45 is replaced by methionine, an amino acid with similar properties. In one study, this variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In another study, this alteration was detected in 1/6385 invasive epithelial ovarian cancer cases and 0/6115 controls of broad European ancestry (Song H et al. J Med Genet, 2021 May;58:305-313). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration has also been identified in a pediatric patient with hypodiploid acute lymphoblastic leukemia (Zhang J et al. N Engl J Med 2015 Dec;373(24):2336-2346). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000903493.4

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

Description

This missense variant replaces threonine with methionine at codon 45 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with sarcoma (PMID: 27498913), colorectal cancer (PMID 28944238) and unspecified pediatric cancer (PMID: 26580448). This variant has been identified in 8/282548 chromosomes 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.

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

From Sema4, Sema4, SCV002537051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

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

Last Updated: Oct 8, 2024

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