chr22-28734600-G-A

Variant names:

• chr22-28734600-G-A
• rs121908694
• NM_007194.4:c.122C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_007194.4(CHEK2):​c.122C>T​(p.Ser41Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 6.24
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32910788).
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.122C>T	p.Ser41Phe	missense	Exon 2 of 15	NP_009125.1
	CHEK2	NM_001005735.3		c.122C>T	p.Ser41Phe	missense	Exon 2 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.122C>T	p.Ser41Phe	missense	Exon 2 of 16	NP_001425222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.122C>T	p.Ser41Phe	missense	Exon 2 of 15	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.122C>T	p.Ser41Phe	missense	Exon 2 of 16	ENSP00000372023.2
	CHEK2	ENST00000402731.6	TSL:1	c.122C>T	p.Ser41Phe	missense	Exon 1 of 13	ENSP00000384835.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.122C>T (p.Ser41Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251096 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.122C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Stolarova_2023). These results showed no damaging effect of this variant. The following publication have been ascertained in the context of this evaluation (PMID: 37449874). ClinVar contains an entry for this variant (Variation ID: 126898). Based on the evidence outlined above, the variant was classified as uncertain significance.

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S41F variant (also known as c.122C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 122. The serine at codon 41 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Starlova, L et al. Clin Cancer Res 2023 Aug;29(16):3037-3050). This amino acid position is highly 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.

Jan 27, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with phenylalanine at codon 41 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 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.

Familial cancer of breast Uncertain:2

Oct 22, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the CHEK2 protein (p.Ser41Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 126898). 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. 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.

not provided Other:1

Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.33	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Benign	0.28	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.28		Loss of phosphorylation at S41 (P = 0.0043)
MVP		0.96
MPC		0.17
ClinPred		0.90	D
GERP RS		5.3
PromoterAI		0.0050	Neutral
Varity_R		0.16
gMVP		0.38
Mutation Taster		=41/59	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: rs121908694; hg19: chr22-29130588;