22-28719415-G-C

Variant names:

• chr22-28719415-G-C
• rs200451612
• NM_007194.4:c.663C>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001257387.2(CHEK2):​c.-1C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,589,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: CHEK2 NM_001257387.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4 O:1
• Conservation: PhyloP100: 1.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07397741).
• BP6: Variant 22-28719415-G-C is Benign according to our data. Variant chr22-28719415-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142342.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.663C>G	p.Ile221Met	missense_variant	Exon 5 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.663C>G	p.Ile221Met	missense_variant	Exon 5 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000437 AC: 10 AN: 228874 Hom.: 0 AF XY: 0.0000324 AC XY: 4 AN XY: 123594

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.0000944

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 27 AN: 1437434 Hom.: 1 Cov.: 27 AF XY: 0.0000168 AC XY: 12 AN XY: 714216

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.0000948

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74428

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000457 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000416 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:3 Benign:1

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Jun 13, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 221 of the CHEK2 protein (p.Ile221Met). This variant is present in population databases (rs200451612, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 142342). 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 does not substantially affect CHEK2 function (PMID: 30851065, 37449874). 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. -

Feb 06, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with methionine at codon 221 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function. Functional studies have shown this variant to have neutral effect on CHEK2 protein function in a DNA damage repair assay in yeast (PMID: 30851065) and no impact on CHEK2 autophosphorylation and KAP1 phosphorylation in a human cell complementation assay (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 32936981). In a case-control meta-analysis, this variant was reported in 7/73048 breast cancer cases and 7/88658 unaffected controls (PMID: 37449874). This variant has also been identified in 16/260244 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in seven females over age 70 who lack personal history of cancer (FLOSSIES, https://whi.color.com/variant/22-29115403-G-C). 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. -

Jul 21, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dec 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:2

Aug 12, 2024

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 indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 19782031, 21244692, 26787654, 27153395, 32936981, 22419737, 37449874, 30851065, 32832836) -

Jun 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.663C>G (p.Ile221Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast/ovarian cancer (PMIDs: 21244692 (2011), 27153395 (2016), 32936981 (2021)). Functional studies reported this variant to have no damaging effect on CHEK2 function (PMIDs: 30851065 (2019), 37449874 (2023)). The frequency of this variant in the general population, 0.00052 (12/22912 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

CHEK2-related disorder Uncertain:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.-1C>G variant is located in the 5' untranslated region. This variant has been identified in 4 individuals with breast and/or ovarian cancer (Supplementary Table 1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Table S4, Maxwell et al. 2016. PubMed ID: 27153395). Functional assessment using a combination of silico tools produced conflicting results, however assessment using a yeast functional assay suggested this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant has been observed with a subpopulation frequency of 0.05% in the gnomAD database, which may be too common to be a primary cause of disease. This variant is classified in ClinVar as uncertain significance (7) and likely benign (4) (https://www.ncbi.nlm.nih.gov/clinvar/variation/142342/). Although, we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colon cancer Uncertain:1

Jan 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 09, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.663C>G (p.Ile221Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 231092 control chromosomes (gnomAD, Le Calves-Kelm_2011), predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database, which is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). Additionally, the variant was reported in 6/2559 African American women (carrier frequency of 0.002345), who were older than 70 years of age with no personal history of cancer (FLOSSIES database). These data suggest that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.663C>G has been reported in the literature in one individual affected with Breast Cancer, without evidence for causality (e.g. Le Calvez-Kelm 2011). Experimental evidence from a yeast complementation assay (Delimitsou_2019), CHEK2-complementation assay, and KAP1 phosphorylation assays (Stolarova_2023) indicated that the variant did not have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 21244692, 27720647, 37449874, 26787654). ClinVar contains an entry for this variant (Variation ID: 142342). Based on the evidence outlined above, the variant was classified as likely benign. -

Predisposition to cancer Benign:1

Sep 14, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.663C>G (p.Ile221Met) missense change has a maximum subpopulation frequency of 0.052% in gnomAD v2.1.1 and a maximum subpopulation frequency of 0.096% in gnomAD v3.2.1. The in silico tool REVEL predicts a benign effect on protein function and functional studies are in agreement with this prediction. A yeast-based growth assay indicated that this variant behaved similar to the wild-type (PMID: 30851065) and CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells also indicated that this variant behaved similar to wild-type (PMID: 37449874). Although this variant has been reported in an individual diagnosed with breast cancer prior to age 45 (PMID: 21244692), seven individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com). In summary, this variant meets criteria to be classified as likely benign. -

CHEK2-related cancer predisposition Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 11-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;T;T;.;T;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	.;D;.;.;D;D;D;.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.074	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L;.;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.84	N;N;N;N;N;.;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.11	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;.;T;T;T
Polyphen		0.95	P;D;P;P;P;P;D;D;.
Vest4		0.60
MVP		0.54
MPC		0.15
ClinPred		0.097	T
GERP RS		5.5
Varity_R		0.61
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200451612; hg19: chr22-29115403;