rs730881681

Variant names:

• chr22-28725365-A-G
• rs730881681
• NM_007194.4:c.322T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-28725365-A-G
• chr22-28725365-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BS2_Supporting

The NM_007194.4(CHEK2):​c.322T>C​(p.Cys108Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000753 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. C108S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10
• Conservation: PhyloP100: 7.10
• Publications: 8 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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 66 uncertain in NM_007194.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• BS2: High AC in GnomAdExome4 at 11 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.322T>C	p.Cys108Arg	missense_variant, splice_region_variant	Exon 3 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.322T>C	p.Cys108Arg	missense_variant, splice_region_variant	Exon 3 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111972

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:5

Mar 08, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 108 of the CHEK2 protein (p.Cys108Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 32660107, 34326862). ClinVar contains an entry for this variant (Variation ID: 182424). 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). 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. -

Apr 04, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 09, 2019

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

To our knowledge, this sequence variant has not been previously reported in the literature. This variant is not present in population databases https://gnomad.broadinstitute.org/. In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. -

Mar 13, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PM2_SUP, PP3 -

not provided Pathogenic:1 Uncertain:2

Sep 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced response to DNA damage in a yeast-based assay (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 29522266, 22419737, 19782031, 31398194, 30851065, 34326862, 28779002, 32660107) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: PS3, PM2_supporting, PP3_moderate -

Hereditary cancer-predisposing syndrome Uncertain:3

Oct 12, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with arginine at codon 108 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). A functional study has shown this variant to be damaging in DNA damage response assay in yeast (PMID: 30851065). 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. -

Nov 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C108R variant (also known as c.322T>C), located in coding exon 2 of the CHEK2 gene, results from a T to C substitution at nucleotide position 322. The cysteine at codon 108 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was also detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). Additionally, this alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This alteration was also reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mar 25, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria has been used according to CanVIG CHEK2 guidelines: PM2_SUP; PP3; PS3_MOD. OR is currently unknown -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T;T;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;T;.;.;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.;M;M;.;.;.;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;.;D;D;D;.;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.013	D;D;D;D;D;.;D;D;D;.;.;.
Sift4G	Benign	0.065	T;D;T;T;D;.;D;D;D;D;.;.
Polyphen		0.99	D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.89
MutPred		0.56		Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);.;Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);.;Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);Loss of catalytic residue at D111 (P = 0.0842);
MVP		0.96
MPC		0.18
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.81
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730881681; hg19: chr22-29121353;