rs531398630

Positions:

chr22-28695858-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_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).

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:14B:4

Conservation

PhyloP100: 8.67

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 -5 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes 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/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1111C>T	p.His371Tyr	missense_variant	11/15	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.1111C>T	p.His371Tyr	missense_variant	11/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

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

GnomAD3 exomes

AF:

0.000477

AC:

119

AN:

249248

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

135238

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 SAS exome

AF:

0.00111

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00217

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000145

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000212

ExAC

AF:

0.000478

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 30, 2021	- -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CHEK2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 15, 2021	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

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2023

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

Uncertain significance, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Aug 31, 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.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:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2024

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

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

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;.;.

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

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

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