22-28734427-G-A

Position:

chr22-28734427-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007194.4(CHEK2):c.295C>T(p.Leu99Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,986 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. L99H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.61

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24447784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.295C>T	p.Leu99Phe	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.295C>T	p.Leu99Phe	missense_variant	2/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251170

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

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:

0.00000410

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

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:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000962

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2023	The p.L99F variant (also known as c.295C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 295. The leucine at codon 99 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration 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 highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2021

Variant summary: CHEK2 c.295C>T (p.Leu99Phe) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.295C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2017

This variant is denoted CHEK2 c.295C>T at the cDNA level, p.Leu99Phe (L99F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu99Phe was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Leu99Phe occurs at a position that is conserved across species and is located in the Forkhead-associated (FHA) domain (Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Leu99Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 449723). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (rs537051622, gnomAD 0.03%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 99 of the CHEK2 protein (p.Leu99Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.24

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

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.1

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.5

D;D;D;D;N;.;N;D;D;D;N;.;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.027

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

Sift4G

Benign

0.21

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

Polyphen

0.98

D;D;D;D;D;D;B;D;.;.;.;.;.

Vest4

0.49

MutPred

0.43

Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);Loss of stability (P = 0.1356);

MVP

0.92

MPC

0.17

ClinPred

0.27

GERP RS

4.4

Varity_R

0.50

gMVP

0.16

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