rs750393263

Positions:

• chr22-28725292-C-A
• chr22-28725292-C-G
• chr22-28725292-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_007194.4(CHEK2):​c.395G>T​(p.Arg132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. R132K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0760

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.

• PM1: In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 27 pathogenic changes around while only 5 benign (84%) in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104533374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.395G>T	p.Arg132Ile	missense_variant	3/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.395G>T	p.Arg132Ile	missense_variant	3/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

Gnomad AFR exome AF: 0.0000615

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 Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2020

This variant has not been reported in the literature in individuals with CHEK2-related conditions. This variant is present in population databases (rs750393263, ExAC 0.01%). This sequence change replaces arginine with isoleucine at codon 132 of the CHEK2 protein (p.Arg132Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	0.20
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Uncertain	0.53	D;.;D;D;.;D;.;.;.;D;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;D;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.047	D;T;D;D;T;.;T;D;D;.;.;.
Sift4G	Benign	0.21	T;T;T;T;T;.;T;T;T;D;.;.
Polyphen		0.096	B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.46
MutPred		0.49		Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);.;Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);.;Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);Loss of disorder (P = 0.0213);
MVP		0.79
MPC		0.033
ClinPred		0.070	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.34

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: rs750393263; hg19: chr22-29121280; COSMIC: COSV60418182; COSMIC: COSV60418182;