22-28696959-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3_StrongPP5

The NM_007194.4(CHEK2):c.1037G>A(p.Arg346His) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,002 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. R346C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9O:1

Conservation

PhyloP100: 6.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28696960-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142222.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=14, Likely_pathogenic=4}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 22-28696959-C-T is Pathogenic according to our data. Variant chr22-28696959-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182431.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=9, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.1037G>A	p.Arg346His	missense_variant	Exon 10 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.1037G>A	p.Arg346His	missense_variant	Exon 10 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251242

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135800

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460894

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:3

Jun 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 37449874, 34903604, 31050813]. This variant is expected to disrupt protein structure [PMID: 16794575]. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 346 of the CHEK2 protein (p.Arg346His). This variant is present in population databases (rs730881688, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 26822949, 31050813, 34326862, 35534704). ClinVar contains an entry for this variant (Variation ID: 182431). 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, 31050813, 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. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Dec 09, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 346 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Experimental studies have shown a deleterious effect on protein function in CHEK2 kinase activity studies (PMID 31050813, 34903604, 37449874) and in a yeast-based DNA damage repair assay (PMID 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 26822949, 29522266, 31050813, 33471991, 37449874) and prostate cancer in the literature (PMID: 31214711). However, a meta-analysis of 12 case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls, did not report a significant association between this variant and breast cancer due to too few affected cases (PMID: 37449874; OR=3.6411, 95% CI 0.735-18.041, P = 0.1135 at medcalc.org). This variant has been identified in 3/282644 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R346H variant (also known as c.1037G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1037. The arginine at codon 346 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was detected in conjunction with another CHEK2 alteration (p.E239K) in 1/1303 female breast cancer cases and 0/1109 cancer-free controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13(1):R6). In another large study, this variant was reported in 6/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Several other studies have reported this alteration in individuals suspected to be affected with hereditary breast cancer (Young EL et al. J Med Genet, 2016 06;53:366-76; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). Earlier functional analyses for this alteration reported neutral or conflicting results (Kleiblova P. Int J Cancer. 2019 10;145(7):1782-1797; Kleiblová P. et al Klin Onkol. 2019;32(Supplementum2):36-50), but this variant was reported as non-functional in a yeast-based assay (Delimitsou A et al. Hum Mutat. 2019 May;40(5):631-648 ), and more recent studies performed in murine embyonic and human cell lines support a deleterious impact (Boonen RACM et al. Cancer Res, 2022 02;82:615-631; Stolarova 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, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Pathogenic:1Uncertain:1

Aug 30, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000023 (3/129024 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 21244692 (2011), 31050813 (2019)) and in breast cancer cases and controls in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). In addition, this variant was demonstrated to have a damaging effect on CHEK2 protein function in functional analyses (PMID: 30851065 (2019) and 34903604 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 23, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with personal and/or family history of breast cancer (PMID: 21244692, 29522266, 31050813, 34903604, 37449874); Published functional studies demonstrate a damaging effect: impaired auto-phosphorylation, reduced/absent kinase activity, and defective DNA-damage response in yeast and cell-based assays (PMID: 30851065, 39146382, 31050813, 34903604); 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; Also known as c.1166G>A, p.(R389H); This variant is associated with the following publications: (PMID: 27071721, 27294619, 31056747, 26424751, 26787654, 21244692, 28188106, 27191893, 29522266, 30851065, 31050813, 33471991, 31206626, 26822949, 37449874, 36243179, 22419737, 19782031, 39642869, 34326862, 34903604, 35534704, 38415346, 39146382) -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Mar 07, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Dec 18, 2023

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.1037G>A (p.Arg346His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719); Serine/threonine-protein kinase, active site (IPR008271) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-06 in 260390 control chromosomes (gnomAD, publications). c.1037G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer or Bilary tract cancer (examples: Okawa_2023, deOliveira_2021, Dorling_2021, Kleiblova_2019, Lhota_2016, Le Calvez-Kelm_2011), but the variant was also transmitted to unaffected individuals within a family, albeit the age of the unaffected individuals with the variant was early 40s (Kleiblova_2019). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function: in vitro assays showed the variant protein had reduced ability to phosphorylate target substrate (Kleiblova_2019), and a functional yeast assay using a DNA repair deficient yeast strain showed the variant protein was incapable of rescuing cell growth and proliferation following MMS induced DNA damage (Delimitsou_2019). The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 33471991, 31050813, 21244692, 26822949, 36243179, 35534704). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Predisposition to cancer

Uncertain:1

Jun 04, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.1037G>A (p.Arg346His) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies support a deleterious impact (PMID: 30851065, 31050813, 34903604). This variant has been observed in individuals with breast cancer (PMID: 21244692, 26822949, 31050813). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

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 12-21-2017 by 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;T;.;T;.;T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;.;D;.;D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.4

M;M;.;M;.;M;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.7

D;D;.;D;D;.;D;D;.

REVEL

Pathogenic

0.72

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

0.94

Gain of disorder (P = 0.0864);Gain of disorder (P = 0.0864);.;Gain of disorder (P = 0.0864);.;Gain of disorder (P = 0.0864);.;.;.;

MVP

0.90

MPC

0.17

ClinPred

1.0

GERP RS

5.7

Varity_R

0.95

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over