chr22-28696957-C-T

Variant names:

• chr22-28696957-C-T
• rs28909980
• NM_007194.4:c.1039G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PP3_Moderate PP5 BS2_Supporting

The NM_007194.4(CHEK2):​c.1039G>A​(p.Asp347Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D347G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:2
• Conservation: PhyloP100: 6.20
• Publications: 18 publications found

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 69 uncertain in NM_007194.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 22-28696957-C-T is Pathogenic according to our data. Variant chr22-28696957-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182432.
• BS2: High AC in GnomAdExome4 at 40 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1039G>A	p.Asp347Asn	missense_variant	Exon 10 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1039G>A	p.Asp347Asn	missense_variant	Exon 10 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251260 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461106 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 18 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111386

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000183 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:3 Uncertain:2

Dec 14, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data, PMID: 19782031, 16794575]. Functional studies indicate this variant impacts protein function [PMID: 19782031, 16794575, 37449874, 34903604]. -

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 347 of the CHEK2 protein (p.Asp347Asn). This variant is present in population databases (rs28909980, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26681312, 30303537, 34903604). ClinVar contains an entry for this variant (Variation ID: 182432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 34903604). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 01, 2024

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Dec 29, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: loss of kinase activity, diminished growth rate after DNA damage (Ghosh 2006, Delimitsou 2019, Boonen 2021); 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 (Lek 2016); Also known as c.1168G>A p.D390N; This variant is associated with the following publications: (PMID: 22419737, 17178848, 20160490, 21618645, 16794575, 19782031, 22159226, 9836640, 21153778, 10673500, 11085506, 29522266, 30851065, 30303537, 26681312, 34903604, 34803902) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHEK2: PM1, PS4:Moderate, PM2:Supporting, PS3:Supporting -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 30, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D347N variant (also known as c.1039G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1039. The aspartic acid at codon 347 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439). In multiple assays testing CHEK2 function, this variant showed functionally abnormal results (Ghosh JC et al. Cancer Res., 2006 Dec;66:11576-9; Delimitsou A et al. Hum. Mutat., 2019 Mar; Boonen RACM et al. Cancer Res, 2022 02;82:615-631; Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This alteration occurs at a critical catalytic residue in the highly conserved kinase domain of CHEK2; and based on internal structural assessment, this alteration disrupts conserved specific catalytic interactions in the active site (Ambry internal data; Oliver AW et al. EMBO J., 2006 Jul;25:3179-90; Cai Z et al. Mol. Cell, 2009 Sep;35:818-29). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 347 in the kinase domain of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown this variant to be damaging to CHEK2 function in a DNA damage repair assay in yeast (PMID: 30851065) and that this variant impacts CHEK2 function in autophosphorylation and phosphorylation of KAP1 in mammalian cells (PMID: 34903604, 37449874). This variant has been reported in seven individuals affected with breast cancer, including three individuals having familial breast cancer (PMID: 26681312, 28779002, 30303537; Color internal data). This variant has been reported in two large case-control meta-analyses, in 4/60466 cases and 4/53461 unaffected controls (PMID: 33471991; p-value=1; Leiden Open Variation Database DB-ID CHEK2_000374) and 6/73048 cases and 4/88658 controls (PMID: 37449874). This variant has been identified in 3/251260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;.;T;.;T;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;.;M;.;M;.;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	D;D;.;D;D;.;D;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;.;D;D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;D;D;D;.;.
Vest4		0.97
MutPred		0.36		Loss of catalytic residue at N352 (P = 0.1251);Loss of catalytic residue at N352 (P = 0.1251);.;Loss of catalytic residue at N352 (P = 0.1251);.;Loss of catalytic residue at N352 (P = 0.1251);.;.;.;
MVP		0.99
MPC		0.16
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28909980; hg19: chr22-29092945;