rs1060502695

Positions:

• chr22-28725344-A-C
• chr22-28725344-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007194.4(CHEK2):​c.343T>G​(p.Phe115Val) 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: 32)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.10

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 5 ACMG points.

• PM1: In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.343T>G	p.Phe115Val	missense_variant	3/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.343T>G	p.Phe115Val	missense_variant	3/15	1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2019

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CHEK2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with valine at codon 115 of the CHEK2 protein (p.Phe115Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2023

The p.F115V variant (also known as c.343T>G), located in coding exon 2 of the CHEK2 gene, results from a T to G substitution at nucleotide position 343. The phenylalanine at codon 115 is replaced by valine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;D;D;.;D;.;.;.;D;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;D;.;.;T;T;.;T;D;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.3	L;L;L;L;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;.;D;D;D;D;.;.
REVEL	Pathogenic	0.77
Sift	Benign	0.041	D;D;D;D;T;.;D;D;T;D;.;.
Sift4G	Benign	0.21	T;T;T;T;T;.;T;T;D;D;.;.
Polyphen		0.25	B;D;B;B;P;B;D;.;.;.;.;.
Vest4		0.86
MutPred		0.58		Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);.;Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);.;Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);Gain of ubiquitination at K119 (P = 0.0831);
MVP		0.92
MPC		0.18
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.64

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: rs1060502695; hg19: chr22-29121332;