rs587782527

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_007194.4(CHEK2):c.1216C>T(p.Arg406Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000638 in 1,613,698 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:1

Conservation

PhyloP100: 3.63

Publications

21 publications found

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 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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40644896).

BS2

High AC in GnomAd4 at 14 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 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 11 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 11 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

250830

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.000201

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1111636

Other (OTH)

AF:

0.0000994

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41554

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000499

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Sep 01, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, this variant has been reported in individuals and families with breast/ovarian cancer (PMIDs: 35402282 (2022), 35264596 (2022), 32885271 (2021), 30303537 (2019), 30441849 (2018), 23806170 (2013), 21244692 (2011), 14618615 (2004)), and prostate cancer (PMID: 29368341 (2018)). It has also been observed in breast cancer cases and unaffected control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). In addition, an experimental study reports this variant has a neutral effect on CHEK2 protein function in yeast (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.00014 (5/35430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jan 01, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.1216C>T; p.Arg406Cys variant (rs587782527) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Isaacsson 2018, Le Calvez-Kelm 2011, Osorio 2004, Rashid 2013), and is reported in ClinVar (Variation ID: 142533). This variant is found in the general population with an overall allele frequency of 0.006% (17/282232 alleles) in the Genome Aggregation Database. The arginine at codon 406 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, an in vivo yeast-based functional assay suggests that this variant is benign (Delimitsou 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. Isaacsson Velho P et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018 Apr;78(5):401-407. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. Osorio A et al. The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer. 2004 Jan 1;108(1):54-6. Rashid MU et al. Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. BMC Cancer. 2013 Jun 27;13:312. -

Sep 23, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 16, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate no damaging effect: similar growth rates to the wild-type in a yeast-based assay (Delimitsou et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history of sarcoma, breast, ovarian, or other cancers (Osorio et al., 2004; Le Calvez-Kelm et al., 2011; Rashid et al., 2013; Ballinger et al., 2016; Girard et al., 2019; Guindalini et al., 2022); Also known as c.1345C>T (p.Arg449Cys); This variant is associated with the following publications: (PMID: 26787654, 23741719, 28514183, 28553140, 25629968, 23806170, 14618615, 27498913, 21244692, 29173497, 28102005, 29368341, 29596542, 30303537, 32322110, 19782031, 22419737, 35495172, 30851065, 35264596) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:3Benign:1

Mar 08, 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]. -

Jan 08, 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 cysteine, which is neutral and slightly polar, at codon 406 of the CHEK2 protein (p.Arg406Cys). This variant is present in population databases (rs587782527, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, hepatoblastoma, and/or ovarian cancer (PMID: 14618615, 21244692, 23806170, 29368341, 32885271, 35402282, 35495172, 35534704, 38061684). ClinVar contains an entry for this variant (Variation ID: 142533). 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). 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. -

Jun 21, 2016

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. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 05, 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 cysteine at codon 406 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported this variant protein as benign in a yeast complementation assay (PMID: 30851065). This variant has been reported in individuals with personal and/or family history of breast and ovarian cancer (PMID: 14618615, 21244692, 23806170, 30441849, 30303537, 32885271, 35402282), prostate cancer (PMID: 29368341), and sarcoma (PMID: 27498913). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 9/60466 cases and 9/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000187). This variant has also been identified in 17/282232 chromosomes 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. -

Feb 14, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R406C variant (also known as c.1216C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1216. The arginine at codon 406 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in numerous disease cohorts (Osorio A et al. Int. J. Cancer. 2004 Jan;108:54-6; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Rashid MU et al. BMC Cancer. 2013 Jun;13:312; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Young EL et al. J Med Genet, 2016 06;53:366-76; Decker B et al. J Med Genet, 2017 11;54:732-741; Isaacsson Velho P et al. Prostate. 2018 Apr;78:401-407; Koczkowska M et al. Cancers (Basel), 2018 Nov;10:; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Feb 21, 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.1216C>T (p.Arg406Cys) results in a non-conservative amino acid change located in the Serine/Threonine protein kinases, catalytic 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 5.1e-05 in 254176 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.1e-05 vs 0.00031), allowing no conclusion about variant significance. However, this observation needs to be cautiously considered since sequence alignment analysis suggests that the variant lies within a region of the gene that has high homology with the CHEK2P2 pseudogene. c.1216C>T has been reported in the heterozygous state in the literature in individuals with personal and/or family history of cancer (e.g. Calvez-Kelm_2011, Rashid_2013, Osorio_2004, Isaacsson_2018, Koczkowska_2018, Girard_2019, Dorling_2021, Guindalini_2022, Stolarova_2023) as well as controls, however segregation data were not found. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 9/60466 cases, but was also found in 9/53461 controls (Dorling_2021, reported through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with CHEK2-related conditions. In a yeast functional study, the variant was found to be benign (Delimitsou_2019), however more relevant functional assays performed in human cell line backgrounds found this variant to be moderately deleterious for both KAP1 phosphorylation and CHEK2 autophosphorylation activity in vitro (example, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 21244692, 30851065, 33471991, 30303537, 35264596, 29368341, 30441849, 14618615, 23806170, 37449874). ClinVar contains an entry for this variant (Variation ID: 142533). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CHEK2-related disorder

Uncertain:1

Sep 14, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.1216C>T variant is predicted to result in the amino acid substitution p.Arg406Cys. This variant has been reported in individuals with breast cancer (Osorio et al. 2004. PubMed ID: 14618615; Table S1 - Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Table S3, Girard et al. 2018. PubMed ID: 30303537; Table S3, Guindalini et al. 2022. PubMed ID: 35264596), an individual with ovarian cancer (Rashid et al. 2013. PubMed ID: 23806170; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849), an individual with prostate cancer (Table S1 - Isaacsson Velho et al. 2018. PubMed ID: 29368341), and an individual with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). Functional studies found this variant does not differ significantly from wild type CHEK2 (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091741-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142533/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast and/or ovarian cancer

Uncertain:1

Jul 05, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Predisposition to cancer

Uncertain:1

Jun 17, 2025

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.1216C>T p.(Arg406Cys) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function. This variant was found to be functional in a yeast-based assay (PMID: 30851065). To our knowledge, this variant has not been reported as pathogenic in individuals with CHEK2-related tumors. 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. -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CHEK2 p.Arg406Cys variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from Pakistani individuals or families with BRCA1/2 negative early-onset and familial breast/ovarian cancers and was not identified in 300 control chromosomes from healthy individuals, or 229 individuals with BRCA1/2 negative breast/ovarian cancers (Rashid 2013). In a yeast complementation assay assessing protein function of the Arg406His variant, the variant did not abrogate CHEK2 function, with yeast cells carrying the Arg406His variant growing at a similar rate to those carrying wildtype (Yilmaz 2014). The variant was also identified in in dbSNP (ID: rs587782527) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Ambry genetics, GeneDx, Invitae, and Counsyl), Clinvitae; and in control databases in 17 of 276708 chromosomes at a frequency of 0.00006 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg406 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys variant may impact the protein; however, this information is not predictive enough to assume 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. -

CHEK2-related cancer predisposition

Uncertain:1

Nov 03, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 406 of the CHEK2 protein (p.Arg406Cys).This amino acid position is moderate conserved (PhyloP=3.6) . This variant is present in population databases (rs587782527, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, hepatoblastoma, and/or ovarian cancer (PMID: 26787654, 23741719, 28514183, 28553140, 25629968, 23806170, 14618615, 27498913, 21244692, 29173497, 28102005, 29368341, 29596542, 30303537, 32322110, 19782031, 22419737, 35495172, 30851065, 35264596). ClinVar contains an entry for this variant (Variation ID: 142533). In addition, the in silico prediction for this alteration is inconclusive. Experimental studies have shown that this missense change does not substantially affect 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. Pathogenic/likely pathogenic variants in the CHEK2 gene cause susceptibility to breast cancer (OMIM 114480). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.039

MetaRNN

Benign

0.41

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

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.4

L;.;L;.;L;.;L;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.28

Sift

Benign

0.077

T;T;T;.;T;D;.;D;T

Sift4G

Benign

0.061

T;T;T;.;T;T;.;D;T

Polyphen

0.74

P;D;P;.;P;P;P;D;D

Vest4

0.77

MutPred

0.58

Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;Gain of catalytic residue at V408 (P = 0.0684);.;.;

MVP

0.76

MPC

0.038

ClinPred

0.58

GERP RS

4.7

Varity_R

0.38

gMVP

0.66

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over