rs766462610

chr22-28710050-G-Achr22-28710050-G-Cchr22-28710050-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007194.4(CHEK2):c.802C>T(p.Leu268Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. L268V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15320915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.802C>T	p.Leu268Phe	missense_variant	7/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.802C>T	p.Leu268Phe	missense_variant	7/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250130 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135394

Gnomad AFR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408138 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 703290

Gnomad4 AFR exome AF: 0.00

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: 9.39e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2022	The p.L268F variant (also known as c.802C>T), located in coding exon 6 of the CHEK2 gene, results from a C to T substitution at nucleotide position 802. The leucine at codon 268 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2017

This variant is denoted CHEK2 c.802C>T at the cDNA level, p.Leu268Phe (L268F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu268Phe was not observed at a significant allele 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 Leu268Phe occurs at a position that is not conserved and is located in the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Leu268Phe 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

Jan 25, 2024

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 268 of the CHEK2 protein (p.Leu268Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 449980). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Benign	0.92
DEOGEN2	Benign	0.080	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L;L;L;.;L;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.62	N;N;N;.;N;N;.;N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.16	T;T;T;.;T;T;.;T;T;T;.;T
Sift4G	Benign	0.10	T;T;T;.;T;T;.;T;T;T;.;.
Polyphen		0.0	B;B;B;.;B;B;B;B;B;.;.;.
Vest4		0.17
MutPred		0.53		Gain of catalytic residue at P266 (P = 0.1629);Gain of catalytic residue at P266 (P = 0.1629);Gain of catalytic residue at P266 (P = 0.1629);.;Gain of catalytic residue at P266 (P = 0.1629);.;Gain of catalytic residue at P266 (P = 0.1629);.;Gain of catalytic residue at P266 (P = 0.1629);.;.;.;
MVP		0.95
MPC		0.020
ClinPred		0.21	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.32

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

Other links and lift over

dbSNP: rs766462610; hg19: chr22-29106038; COSMIC: COSV104653603; COSMIC: COSV104653603;