rs730881694

Positions:

• chr22-28734576-G-A
• chr22-28734576-G-C
• chr22-28734576-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.146C>T​(p.Ser49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S49C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.92

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=0.2020793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.146C>T	p.Ser49Phe	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.146C>T	p.Ser49Phe	missense_variant	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22114986, 11733767, 29641532, 34480478) -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the CHEK2 protein (p.Ser49Phe). This variant is not present in population databases (gnomAD no frequency). 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: 219642). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 01, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2022	This missense variant replaces serine with phenylalanine at codon 49 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 16, 2023	The p.S49F variant (also known as c.146C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 146. The serine at codon 49 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	0.76	D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;N;N;N;.;N;N;N;N;N;.;N
REVEL	Benign	0.082
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;D;D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen		0.36	B;P;B;B;P;B;P;P;.;.;.;.;.
Vest4		0.29
MutPred		0.13		Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);Loss of phosphorylation at S49 (P = 0.0017);
MVP		0.96
MPC		0.17
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.099
gMVP		0.30

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: rs730881694; hg19: chr22-29130564; COSMIC: COSV60418671; COSMIC: COSV60418671;