22-28695828-T-C

Position:

chr22-28695828-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_007194.4(CHEK2):c.1141A>G(p.Met381Val) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 5.16

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1141A>G	p.Met381Val	missense_variant	11/15	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.1141A>G	p.Met381Val	missense_variant	11/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152218

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250916

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1461528

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000157

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 381 of the CHEK2 protein (p.Met381Val). This variant is present in population databases (rs375130261, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 25186627, 28944238, 30613976, 32959997). This variant is also known as c.1270A>G or p.Met424Val. ClinVar contains an entry for this variant (Variation ID: 140959). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 26, 2023	BS3_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	Published functional studies suggest no damaging effect: demonstrates auto-phosphorylation and/or kinase activity similar to wild type in yeast and human cell-based assay(s) (PMID: 30851065, 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: 31398194, 27535334, 28944238, 29981437, 30269267, 25186627, 30613976, 32959997, 35264596, 32885271, 36717774, 30851065, 19782031, 22419737, 35493704, 35957908, 35534704, 37449874) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2023	This missense variant replaces methionine with valine at codon 381 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). Functional studies have shown no significant impact of this variant on DNA damage repair activity in yeast (PMID: 30851065) and intermediate impact on KAP1 phosphorylation and no impact on CHEK2 autophosphorylation in mammalian cells (PMID: 37449874). This variant has been reported in individuals affected with breast, pancreatic, and colorectal cancer (PMID: 25186627, 28944238, 32885271, 32959997, 36717774) and in one unaffected individual (PMID: 37449874). This variant has been identified in 10/282330 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2022	The p.M381V variant (also known as c.1141A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1141. The methionine at codon 381 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in a cohort of 1231 colorectal cancer cases (DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5:553-569) and in a woman with breast cancer undergoing multi-gene panel testing (Tung N et al. Cancer, 2015 Jan;121:25-33). This variant was also observed in 4/3251 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). 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 highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 13, 2018

Variant summary: CHEK2 c.1141A>G (p.Met381Val) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1141A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

The CHEK2 c.1141A>G variant is predicted to result in the amino acid substitution p.Met381Val. This variant has been identified in an individual with colorectal cancer (Table S2, DeRycke et al. 2017. PubMed ID: 28944238), and in several individuals with breast cancer, including male breast cancer (Uyisenga et al 2020. PubMed ID: 32959997; Rizzolo P et al 2019. PubMed ID: 30613976; de Oliveira JM et al 2022. PubMed ID: 35534704; Tung N et al 2014. PubMed ID: 25186627). This variant has also been called c.1270A>G or p.Met424Val in the literature. This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091816-T-C) and is classified in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/140959/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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.Met381Val variant was not identified in the literature nor was it identified in the MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in the following databases: dbSNP (ID: rs375130261) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae, and Cosmic. The variant was identified in control databases in 11 of 276850 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34410 chromosomes (freq: 0.00003), European in 10 of 126376 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met381 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.67

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

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.33

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.5

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

REVEL

Uncertain

0.44

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.011

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

Polyphen

0.94

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

Vest4

0.82

MVP

0.77

MPC

0.12

ClinPred

0.65

GERP RS

5.9

Varity_R

0.82

gMVP

0.68

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