rs767758092

Variant names:

• chr22-28734434-T-A
• rs767758092
• NM_007194.4:c.288A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28734434-T-A
• chr22-28734434-T-C

Variant summary

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

The NM_001257387.2(CHEK2):​c.-490A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_001257387.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.162

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.288A>T	p.Leu96Phe	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	c.288A>T	p.Leu96Phe	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 96 of the CHEK2 protein (p.Leu96Phe). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. ClinVar contains an entry for this variant (Variation ID: 1035250). -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L96F variant (also known as c.288A>T), located in coding exon 1 of the CHEK2 gene, results from an A to T substitution at nucleotide position 288. The leucine at codon 96 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial prostate cancer Uncertain:1

Nov 29, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D;D;D;D;N;.;N;D;D;D;D;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.026	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;.;T;D;D;D;D;.;.
Polyphen		0.99	D;P;D;D;D;D;D;P;.;.;.;.;.
Vest4		0.54
MutPred		0.65		Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);Loss of stability (P = 0.1694);
MVP		0.95
MPC		0.13
ClinPred		0.98	D
GERP RS		-5.6
Varity_R		0.66
gMVP		0.28

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: rs767758092; hg19: chr22-29130422;