rs765799649

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.164C>T(p.Ser55Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,796 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 3.53

Publications

2 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=0.37952483).

BS2

High AC in GnomAd4 at 5 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.164C>T	p.Ser55Phe	missense_variant	Exon 2 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.164C>T	p.Ser55Phe	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251444

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000274

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000329

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41344

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.0000329

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Jan 25, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S55F variant (also known as c.164C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 164. The serine at codon 55 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367; van der Merwe NC et al. Front Oncol, 2022 Dec;12:938561). In addition, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M. JCO Precis Oncol . 2020 Jan;4:32-43). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a high grade glioma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). 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. -

Dec 13, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with phenylalanine at codon 55 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit near normal activity in a yeast-based DNA damage repair / complementation assay (PMID: 22006311). This variant has been reported in an individual affected with a carcinoma of ovarian, fallopian tube, or peritoneal origin in the literature (PMID: 22006311) and in an individual affected with breast cancer who also carried a pathogenic variant in the BRCA2 gene (PMID: 31871109). This variant has been identified in 2/251444 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. -

not provided

Uncertain:2

Apr 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate no damaging effect: DNA damage response, auto-phosphorylation, and kinase activity comparable to wildtype (PMID: 37449874, 22006311); Observed in individuals with breast cancer, gynecologic cancer, prostate cancer, or glioma (PMID: 22006311, 32832836, 26580448, 37449874); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32832836, 26580448, 37449874, 11733767, 22114986, 22006311, 31871109) -

Apr 13, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 55 of the CHEK2 protein (p.Ser55Phe). This variant is present in population databases (rs765799649, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian, peritoneal or fallopian tube cancer (PMID: 22006311, 31871109). ClinVar contains an entry for this variant (Variation ID: 410069). 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 does not substantially affect CHEK2 function (PMID: 22006311). 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. -

Mar 06, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 22, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Predisposition to cancer

Uncertain:1

Jul 06, 2023

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.164C>T (p.Ser55Phe) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and a yeast-based assay has shown that this variant is able to complement DNA damage hypersensitivity comparable to wild-type CHEK2 (PMID: 22006311). This variant has been identified in an individual with breast cancer who also harbored a pathogenic variant in BRCA2 (PMID: 31871109). It has also been identified in at least one African male with prostate cancer (PMID: 32832836, 36898365) and one female with a reproductive tract cancer where the wild-type allele was not lost in the tumor (PMID: 22006311). 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. -

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

Uncertain:1

May 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

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

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.049

MetaRNN

Benign

0.38

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

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.3

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

PhyloP100

3.5

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.23

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.13

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

Vest4

0.35

MVP

0.94

MPC

0.17

ClinPred

0.90

GERP RS

5.4

PromoterAI

0.0019

Neutral

(source)

Varity_R

0.34

gMVP

0.47

Mutation Taster

=55/41

polymorphism

(source)

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

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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