rs121908705

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007194.4(CHEK2):c.1336A>G(p.Asn446Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. N446K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:4O:1

Conservation

PhyloP100: 3.57

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:

CHEK2 (HGNC:):

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07117692).

BP6

Variant 22-28695166-T-C is Benign according to our data. Variant chr22-28695166-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126909.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=10, not_provided=1}. Variant chr22-28695166-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1336A>G	p.Asn446Asp	missense_variant	12/15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1336A>G	p.Asn446Asp	missense_variant	12/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251088

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135688

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:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461152

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000302

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -
not provided, no classification provided	literature only	Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, rectal cancer, or lymphoma and in unaffected controls (Le Calvez-Kelm 2011, Havranek 2015, Kraus 2016, Pearlman 2017); Published functional study demonstrates no damaging effect: normal cell growth after MMS-induced DNA damage (Delimitsou 2019); This variant is associated with the following publications: (PMID: 26506619, 21244692, 27978560, 27616075, 26787654, 28873162, 29596542, 30851065, 31398194, 31422574, 19782031, 22419737, 34903604) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2020	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2019	Variant summary: CHEK2 c.1336A>G (p.Asn446Asp) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 253306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (7.5e-05 vs 0.00031), allowing no conclusion about variant significance. The variant was reported in breast cancer, colorectal cancer or Non-Hodgkin Lymphoma patients, without strong evidence for causality (Kraus 2016, Havranek 2015, Pearlman 2016), and was also found in healthy controls (Le Calvez-Kelm 2011). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another likely pathogenic variant has been reported in an internal sample (APC c.4873delC, p.Gln1625fsX25). In an in vivo, yeast based functional assay, the variant was classified as benign (Delimitsou_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 446 of the CHEK2 protein (p.Asn446Asp). This variant is present in population databases (rs121908705, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, non-Hodgkin lymphoma, and/or rectal cancer (PMID: 26506619, 27616075, 27978560, 34326862). ClinVar contains an entry for this variant (Variation ID: 126909). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065, 34903604). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 06, 2019	- -

CHEK2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Asn446Asp variant was identified in 3 of 10018 proband chromosomes (frequency: 0.0003) from individuals or families with Non-Hodgkin Lymphoma, breast cancer and colorectal cancer (Havranek 2015, Kraus 2017, Le Calvez-Kelm 2011, Pearlman 2017) and was present in 1 of 3208 control chromosomes (frequency: 0.0003) from healthy individuals (Havranek 2015, Le Calvez-Kelm 2011).The variant was also identified in dbSNP (ID: rs121908705) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Invitae, Color Genomics, Ambry Genetics and 3 clinical laboratories), Clinvitae (classified as uncertain significance by Clinvar and Invitae), MutDB, databases. The variant was not identified in Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 19 of 276858 chromosomes at a frequency of 0.000069 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 9 of 126372 chromosomes (freq: 0.0001), and South Asian in 10 of 30776 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Asn446 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.092

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

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.071

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.74

N;.;N;.;N;.;N;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.79

N;N;N;.;N;N;.;N;N

REVEL

Benign

0.067

Sift

Benign

0.36

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

Sift4G

Benign

0.55

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

Polyphen

0.0030

B;B;B;.;B;B;B;B;B

Vest4

0.33

MutPred

0.34

Loss of methylation at K444 (P = 0.0966);.;Loss of methylation at K444 (P = 0.0966);.;Loss of methylation at K444 (P = 0.0966);.;Loss of methylation at K444 (P = 0.0966);.;.;

MVP

0.76

MPC

0.021

ClinPred

0.054

GERP RS

4.9

Varity_R

0.38

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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