rs531398630

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_007194.4(CHEK2):c.1111C>T(p.His371Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,612,708 control chromosomes in the GnomAD database, including 3 homozygotes. 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. H371R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:4

Conservation

PhyloP100: 8.67

Publications

67 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 -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 57 uncertain in NM_007194.4

BP4

Computational evidence support a benign effect (MetaRNN=0.024323523).

BS2

High AC in GnomAd4 at 22 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.1111C>T	p.His371Tyr	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.1111C>T	p.His371Tyr	missense_variant	Exon 11 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152080

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:

0.00270

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000477

AC:

119

AN:

249248

AF XY:

0.000547

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1460510

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

129

AN XY:

726718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00217

AC:

AN:

39694

South Asian (SAS)

AF:

0.00114

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1110778

Other (OTH)

AF:

0.000166

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000145

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00270

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.00

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000478

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4

Jul 30, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 371 of the CHEK2 protein (p.His371Tyr). This variant is present in population databases (rs531398630, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, diffuse large B-cell lymphoma, gastric cancer and pancreatic cancer, as well as unaffected control subjects (PMID: 16883537, 18484200, 21244692, 21618645, 23960188, 24390236, 27442652, 29338689, 29667044, 32091409, 32521533). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128044). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 21618645, 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. -

not specified

Uncertain:3

Mar 04, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

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.1111C>T (p.His371Tyr) results in a conservative amino acid change located in the Protein kinase domain (IPR099710) 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 0.00051 in 254090 control chromosomes, predominantly at a frequency of 0.0041 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13-fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1111C>T has been reported in the literature in individuals affected with Breast Cancer as well as in unaffected controls in settings of multigene panel testing (e.g. Baloch_2013, LeCalvez-Kelm_2011, Leedom_2016, Young_2016, Liu_2011, Momozawa_2018), in settings of other cancers such as diffuse large B cell lymphomas (e.g. deMiranda_2013) and also in a case report of a reportedly de novo occurrence in a Chinese family with Li-Fraunemi like syndrome (Zhuang_2016). However, the case report of the de novo occurrence is questionable as the parents of the proband were not tested for the variant and the de novo status was interpreted based on the genotypes of her two healthy sisters. Furthermore, the high frequency of this variant among East Asian cohorts casts additional doubt on the strength of this evidence. One group performed a case-control study in a Chinese population that suggested the variant is significantly more frequent in familial breast cancer patients who were negative for mutations in BRCA1/2 than controls (OR = 5.99 [95% CI = 1.98-18.19]; p = 0.002) as well as unselected breast cancer patients (OR = 2.43 [95% CI = 1.07-5.52]; p = 0.034) and suggest the variant confers a moderate risk for breast cancer (Liu_2011). The same study reported incomplete segregation within families and performed functional studies that showed reduced phosphorylation and kinase activity. The variant has also been reported to co-occur with an unspecified pathogenic BRCA2 mutation in at least two breast cancer patients (Liu_2015), excluding the variant as the primary cause of disease in the patients. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least two recent publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human CHECK2-knockout cells (Stolarova_2023) and in a yeast-based experimental system evaluating the ability to resume cell growth and proliferation by repair of methyl-methanesulfonate (MMS) induced DNA damage (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 24390236, 30851065, 21244692, 27751358, 25884806, 21618645, 25629968, 30287823, 26787654, 27442652, 23960188, 37449874). ClinVar contains an entry for this variant (Variation ID: 128044). Based on the evidence outlined above, the variant was classified as a VUS-possibly benign until additional peer derived clinical and functional consensus in the field is established. -

not provided

Uncertain:1Benign:2

Sep 29, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in individuals with breast cancer, but also in unaffected controls (Chen et al., 2008; LeCalvez-Kelm et al., 2011; Baloch et al., 2014; Caminsky et al., 2016; Momozawa et al., 2018; Pfaendler and Randall, 2019; Chen et al., 2020; Lang et al., 2020); Published functional studies are inconclusive/conflicting: decreased phosphorylation and CHEK2 kinase activity in one study, but DNA damage response, cell growth rates, and Kap1 phosphorylation similar to wild-type in other studies (Liu et al., 2011; Delimitsou et al., 2019; Boonen et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.1240C>T; p.His414Tyr; This variant is associated with the following publications: (PMID: 23806170, 16883537, 21618645, 28580595, 31220302, 31296309, 30826992, 31358837, 32801835, 24390236, 25629968, 18484200, 21244692, 27442652, 23960188, 26787654, 26898890, 28152038, 27751358, 28873162, 28961279, 29020732, 23318652, 29338689, 29879026, 29506128, 28301460, 29667044, 29470806, 28553140, 27783279, 27621404, 30723762, 29356917, 30851065, 30630526, 30287823, 31054147, 31472684, 32091409, 33313162, 31742824, 33322746, 30975222, 31980526, 32521533, 34426522, 32906215, 34903604, 31721094, 35643632, 28888541, 34926254, 22419737, 19782031, 25884806, 34282142, 32923877, 34716641, 34630562, 34567566) -

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2: BP4, BS1 -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 22, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2021

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. -

Bone osteosarcoma

Uncertain:1

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.1111C>T(p.His371Tyr) variant in CHEK2 gene has been reported in heterozygous state in individuals with susceptibility to breast cancer (Liu Y, et. al., 2015). The p.His371Tyr variant is reported with an allele frequency of 0.05% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Benign/Likely benign/ Uncertain Significance (multiple submission). The amino acid change p.His371Tyr in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid His at position 371 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Varint of Uncertain Significance (VUS). -

CHEK2-related disorder

Uncertain:1

Mar 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.1111C>T variant is predicted to result in the amino acid substitution p.His371Tyr. This variant has been reported in individuals with multiple types of cancers including: breast (Liu et al. 2011. PubMed ID: 21618645; Baloch et al. 2014. PubMed ID: 24390236; Sung et al. 2017. PubMed ID: 28961279; Chen et al. 2020. PubMed ID: 32091409; Table A2 - Greville-Heygate et al. 2020. PubMed ID: 32923877), ovarian (Table S2 - Li et al. 2019. PubMed ID: 31472684), pancreatic (Lowery et al. 2018. PubMed ID: 29506128; Ohmoto et al. 2018. PubMed ID: 29667044), diffuse large B-cell lymphoma (de Miranda et al. 2013. PubMed ID: 23960188), uterine broad ligament ependymoma (Yin et al. 2021. PubMed ID: 34716641), and an individual with Li–Fraumeni syndrome (Zhuang et al. 2016. PubMed ID: 27442652). Functional studies provide conflicting evidence of this variants impact on function (Liu et al. 2011. PubMed ID: 21618645; Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.42% of alleles in individuals of East Asian descent in gnomAD including in the homozygous state in one individual (http://gnomad.broadinstitute.org/variant/22-29091846-G-A). In ClinVar this variant has conflicting interpretations including benign, likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128044/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lung cancer;C0346153:Familial cancer of breast;C0919267:Ovarian neoplasm

Uncertain:1

Mar 19, 2021

University Health Network, Princess Margaret Cancer Centre

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breast neoplasm

Uncertain:1

Aug 31, 2017

3DMed Clinical Laboratory Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.His371Tyr variant was identified in 57 of 8408 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer, diffuse large B cell lymphomas, or hematologic cancer and was identified in 3 of 2658 control chromosomes (frequency: 0.001) from healthy individuals (Baloch 2014, de Miranda 2013, Eoh 2017, Liu 2015, Le Calvez-Kelm 2011, Rashid 2013). The variant was also identified in dbSNP (ID: rs531398630) as â€š With Likely pathogenic alleleâ€šÃ„Ã¹, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and Quest Diagnostics Nichols Institute San Juan Capistrano), Cosmic, MutDB, and the Zhejiang University Database. The variant was identified in control databases in 119 of 275180 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: â€š Otherâ€šÃ„Ã¹ in 1 of 6440 chromosomes (freq: 0.0002), Latino in 1 of 34404 chromosomes (freq: 0.00003), European in 4 of 125344 chromosomes (freq: 0.00003), East Asian in 80 of 18868 chromosomes (freq: 0.004), and South Asian in 33 of 30782 chromosomes (freq: 0.001); it was not observed in the African, Ashkenazi Jewish, or Finnish populations. The p.His371 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the p.His371Tyr amino acid change is within the activation loop of the CHEK2 kinase domain, which is essential for activation of CHEK2 in response to DNA damage (Baloch 2014). 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. -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.098

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

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.024

MetaRNN

Benign

0.024

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.17

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

PhyloP100

8.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.63

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

REVEL

Benign

0.27

Sift

Uncertain

0.028

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

Sift4G

Uncertain

0.030

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

Polyphen

0.011

B;B;B;.;B;B;B;P;B

Vest4

0.70

MutPred

0.62

Loss of methylation at K373 (P = 0.0644);.;Loss of methylation at K373 (P = 0.0644);.;Loss of methylation at K373 (P = 0.0644);.;Loss of methylation at K373 (P = 0.0644);.;.;

MVP

0.82

MPC

0.021

ClinPred

0.092

GERP RS

5.9

Varity_R

0.33

gMVP

0.51

Mutation Taster

=18/82

disease causing

(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