rs986132746

Variant names:

• chr22-28703557-T-A
• rs986132746
• NM_007194.4:c.856A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28703557-T-A
• chr22-28703557-T-C
• chr22-28703557-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007194.4(CHEK2):​c.856A>T​(p.Ile286Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.24

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.856A>T	p.Ile286Phe	missense_variant	Exon 8 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.856A>T	p.Ile286Phe	missense_variant	Exon 8 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 15, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted CHEK2 c.856A>T at the cDNA level, p.Ile286Phe (I286F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ile286Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Ile286Phe occurs at a position that is conserved across species and is located within the protein kinase domain (Desrichard 2011, 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 Ile286Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Nov 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 449790). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 286 of the CHEK2 protein (p.Ile286Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;D;.;D;.;D;D;D;.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;.;M;.;M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D;D;D;.;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D;D;.;D;D;.;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;.;D;D;D;.;.
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;.;.
Vest4		0.91
MutPred		0.67		Gain of methylation at K287 (P = 0.0739);Gain of methylation at K287 (P = 0.0739);Gain of methylation at K287 (P = 0.0739);.;Gain of methylation at K287 (P = 0.0739);.;Gain of methylation at K287 (P = 0.0739);.;Gain of methylation at K287 (P = 0.0739);.;.;.;
MVP		0.84
MPC		0.18
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs986132746; hg19: chr22-29099545;