NM_007194.4(CHEK2):c.73G>A (p.Val25Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 27, 2023
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:: RCV000129252.15

Allele description [Variation Report for NM_007194.4(CHEK2):c.73G>A (p.Val25Ile)]

NM_007194.4(CHEK2):c.73G>A (p.Val25Ile)

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.73G>A (p.Val25Ile)

HGVS:

NC_000022.11:g.28734649C>T
NG_008150.2:g.12218G>A
NM_001005735.2:c.73G>A
NM_001257387.2:c.-705G>A
NM_001349956.2:c.73G>A
NM_007194.4:c.73G>AMANE SELECT
NM_145862.2:c.73G>A
NP_001005735.1:p.Val25Ile
NP_001336885.1:p.Val25Ile
NP_009125.1:p.Val25Ile
NP_665861.1:p.Val25Ile
LRG_302t1:c.73G>A
LRG_302:g.12218G>A
LRG_302p1:p.Val25Ile
NC_000022.10:g.29130637C>T
NG_008150.1:g.12186G>A
NM_007194.3:c.73G>A
p.V25I

Protein change:

V25I

Links:

dbSNP: rs142243299

NCBI 1000 Genomes Browser:

rs142243299

Molecular consequence:

NM_001257387.2:c.-705G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005735.2:c.73G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349956.2:c.73G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007194.4:c.73G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145862.2:c.73G>A - 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
SCV000184011	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000684684	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 32255556, 33471991, 37373225, 37449874, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184011

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 23, 2022)

germline

clinical testing

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

Citation Link,

SCV000684684

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Citations

PubMed

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

Cremin C, Lee MK, Hong Q, Hoeschen C, Mackenzie A, Dixon K, McCullum M, Nuk J, Kalloger S, Karasinska J, Scudamore C, Kim PTW, Donnellan F, Lam ECS, Lim HJ, Neben CL, Stedden W, Zhou AY, Schaeffer DF, Sun S, Renouf DJ, Schrader KA.

Cancer Med. 2020 Jun;9(11):4004-4013. doi: 10.1002/cam4.2973. Epub 2020 Apr 7.

PubMed [citation]

PMID:: 32255556
PMCID:: PMC7286471

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 Ambry Genetics, SCV000184011.9

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

Description

The p.V25I variant (also known as c.73G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 73. The valine at codon 25 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in 1/177 individuals with pancreatic ductal adenocarcinoma undergoing multi-gene panel testing (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is poorly 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.

#	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, SCV000684684.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces valine with isoleucine at codon 25 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). In complementation assays in human CHEK2-knockout cells, this variant did not impact CHK2 autophosphorylation or KAP1 phosphorylation (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 37373225) and pancreatic cancer (PMID: 32255556). This variant has been reported in two breast cancer case-control meta analyses; in 2/73048 cases and 1/88658 controls (PMID: 37449874) and 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991;Leiden Open Variation Database DB-ID CHEK2_000595). This variant has been identified in 3/248530 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

Last Updated: Oct 20, 2024

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