rs587782471

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The ENST00000404276.6(CHEK2):c.707T>C(p.Leu236Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,826 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L236V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:2

Conservation

PhyloP100: 5.68

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000404276.6

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 22-28711994-A-G is Pathogenic according to our data. Variant chr22-28711994-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.13351908). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.707T>C	p.Leu236Pro	missense_variant	6/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.707T>C	p.Leu236Pro	missense_variant	6/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251368

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00252

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461630

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 2021	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported as disease-causing for hereditary beast cancer [PMID:31206626) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 08, 2023	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, flagged submission	clinical testing	Division of Medical Genetics, University of Washington	Aug 30, 2019	The c.836T>C (p.Leu279Pro) variant has an allele frequency of 0.0003112 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect. In addition, a functional assay in yeast demonstrated decreased growth compared to wild type in yeast transfected with the p.Leu279Pro variant [PMID: 30851065]. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Oct 03, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the CHEK2 protein (p.Leu236Pro). This variant is present in population databases (rs587782471, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a strong personal and family history of breast cancer and other cancers, with nearly 80% of these families reporting Hispanic ancestry. In the Hispanic population, this variant has been observed more frequently among individuals with breast cancer than among controls (OR=3.2, 95% CI [1.5-6.5], p=0.0016), and has been reported as a possible founder mutation (PMID: 25186627, 25318351, 31206626; Invitae). ClinVar contains an entry for this variant (Variation ID: 142448). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 13, 2022	In the published literature, this variant has been reported in individuals with early onset breast cancer (PMID: 27621404 (2016), 25186627 (2015), 25318351 (2014)). Recent studies indicate this variant is statistically associated with breast cancer in the Hispanic population (PMID: 31206626 (2019)). In a yeast based functional study, this variant has been shown to have deleterious effects on CHEK2 DNA damage response (PMID: 30851065 (2019)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 12, 2024	PM1, PS3_supporting, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2024	Published functional studies suggest a damaging effect: decreased DNA damage response in a yeast-based assay, impaired KAP1 phosphorylation and CHEK2 auto-phosphorylation in vitro (PMID: 37449874, 30851065); Observed in individuals with breast, prostate, and other cancers (PMID: 32885271, 33471991, 25186627, 37145128, 36833268, 35467778, 38748947); Case-control studies support this variant is associated with breast cancer, particularly in individuals of Hispanic/Latina ancestry (PMID: 37839337, 31206626, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.836T>C, p.L279P; This variant is associated with the following publications: (PMID: 27621404, 25186627, 31398194, 25318351, 32598223, 33471991, 37145128, 30262796, 31206626, 32885271, 37380563, 36833268, 38091153, 37839337, 38093606, 37449874, 38608781, 38735436, Olivares2023[abstract], 34404389, 30851065, 38748947, 19782031, 22419737, 35467778) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 16, 2023	This missense variant replaces leucine with proline at codon 236 in the kinase domain of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Crystal structure studies on CHEK2 place the reference p.Leu236 in the kinase domain near the ATP binding site and implicate it in mediating CHEK2 dimerization, which is required to form an active kinase (PMID: 16794575, 19782031). Functional studies have shown this variant impairs DNA damage response in yeast (PMID: 30851065) and impairs KAP1 phosphorylation and CHK2 autophosphorylation in complementation assays (PMID: 37449874). In the general population, this variant has been reported exclusively in the Latino population and identified in 88/35436 Latino chromosomes by the Genome Aggregation Database (gnomAD). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 30262796, 33471991). A breast cancer case-control study in the Latino population has shown that this variant is associated with increased breast cancer risk with odds ratio of 3.2 (95% CI, 1.5-6.5; P = .002) (PMID: 31206626). This variant has been observed at an increased frequency in individuals affected with breast cancer than in unaffected individuals (Color internal data). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2024	The p.L236P variant (also known as c.707T>C), located in coding exon 5 of the CHEK2 gene, results from a T to C substitution at nucleotide position 707. The leucine at codon 236 is replaced by proline, an amino acid with similar properties. This alteration was non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648). This alteration was also observed with a statistically increased odds ratio in a cohort of Hispanic breast cancer patients compared to general population control carriers (Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836). Additionally, this variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Based on internal structural assessment, this alteration disrupts the fold of the N-lobe of the kinase domain, near the ATP-binding site (Lountos GT et al. J. Struct. Biol. 2011 Dec;176:292-301). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 12, 2023

The CHEK2 c.707T>C (p.Leu236Pro) missense variant has been reported in several individuals with or at elevated risk for primarily breast cancer (PMID: 2531835; 31206626, 32885271, 37145128; DOI:https://doi.org/10.1016/j.clgc.2023.05.012). In a case-control study, p.Leu236Pro was associated with a significantly increased risk of breast cancer risk with an odds ratio of 3.2 (95% CI: 1.5-6.5; p=0.002). It was also reported to have a significant association with estrogen receptor positive tumors (p=0.024) (PMID: 31206626). The highest frequency of this allele in the Genome Aggregation Database is 0.002483 in the Latino/Admixed American population (version 2.1.1), which is higher than expected for a disease-causing variant in this gene. However, it may represent a founder variant in Latin or Indigenous American populations (PMID: 31206626). This variant is in the kinase domain and was shown to impair DNA damage response and growth rate in a yeast-based assay (PMID: 30851065). Based on the collective evidence, the c.707T>C (p.Leu236Pro) variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. -

CHEK2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2024

The CHEK2 c.707T>C variant is predicted to result in the amino acid substitution p.Leu236Pro. This variant has been reported to be significantly enriched in females of Hispanic ancestry with breast cancer when compared to controls (OR=2.41, CI=1.87–3.09, p = 5.35×10^12 in Mundt et al. 2023. PubMed ID: 37839337; Weitzel et al. 2019. PubMed ID: 31206626). This variant occurs in the kinase domain of the CHEK2 protein near the ATP binding site (Oliver et al. 2006. PubMed ID: 16794575; Figure 2, Cai et al. 2009. PubMed ID: 19782031; Lountos et al. 2011. PubMed ID: 21963792; Roeb et al. 2012. PubMed ID: 22419737). In addition to breast cancer, this variant has also been reported in an individual with pediatric onset acute lymphoblastic leukemia (Table S4c_TSG, Zhang et al. 2015. PubMed ID: 26580448) and in individuals undergoing hereditary cancer genetic testing (Table 2, Yorczyk et al. 2015. PubMed ID: 25318351; Table 2, Balmaña et al. 2016. PubMed ID: 27621404). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to be damaging (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD and has not been observed in other ancestral populations. This variant has conflicting interpretations of uncertain and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142448). Based on this evidence, we interpret this variant as likely pathogenic. -

Predisposition to cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 13, 2022

The CHEK2 c.707T>C (p.Leu236Pro) missense change is prevalent in the Latino population with a maximum subpopulation frequency of 0.25% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). A case-control study of BRCA-mutation-negative Hispanic women demonstrated that this variant is associated with increased risk of developing breast cancer in this population, suggesting that this may be a founder variant (PMID: 31206626). The in silico tool REVEL is inconclusive about the effect of this variant on protein function, however an in vivo functional study in yeast suggests a deleterious effect (PMID: 30851065). In summary, this variant meets criteria to be classified as likely pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2024

Variant summary: CHEK2 c.707T>C (p.Leu236Pro) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 0.00035 in 251368 control chromosomes, predominantly at a frequency of 0.0025 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). However, a relatively recent study performed on a large cohort of Hispanics, reported that the variant is observed more frequently in patients affected with breast cancer than in controls, and the variant was reported as a potential founder mutation in this population (Weitzel_2019). c.707T>C has also been reported in the literature in several individuals (mostly of Hispanic/Latin American origin) affected with HBOC and/or with a positive family/personal history for breast cancer (e.g. Tung_2015, Quezada Urban_2018, SoRelle_2020, Dorling_2021, Chavarri-Guerra_2021, Weitzel_2019, Lerner-Ellis_2021) as well as at least one individual affected with prostate cancer (e.g., Brady_2022). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to restrict growth rate levels to those of the negative control strain carrying the well-known pathogenic CHEK2 variant c.1100delC (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 27621404, 35467778, 30851065, 33471991, 34404389, 30262796, 32598223, 25186627, 31206626, 25318351, 26580448, 32975687). ClinVar contains an entry for this variant (Variation ID: 142448). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial cancer of breast;C0677776:Hereditary breast ovarian cancer syndrome;C5882668:Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Jul 17, 2019

The Leu236Pro variant in CHEK2 has been reported in individuals with early onset breast cancer (Yorczyk 2014, Tung 2015, Weitzel 2019). Additionally an in vivo functional study in transformed yeast cells indicates that the Leu236Pro variant are incapable of completing DNA replication and entering mitosis (Delimitsou 2019 -PMID:30851065). Also in our laboratory we have found 9 individuals of Mexican ancestry with breast, ovarian, thyroid and central nervous system tumors and high risk criteria. In summary, the variant meets ACMG criteria to be classified as likely pathogenic. (ACMG criteria: PS3, PM1, PP3, BS2) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

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

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.031

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

0.017

MutationAssessor

Uncertain

2.7

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.2

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.70

Loss of stability (P = 0.0158);Loss of stability (P = 0.0158);Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;.;.;.;

MVP

0.80

MPC

0.18

ClinPred

0.33

GERP RS

5.2

Varity_R

0.98

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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