rs1555913901

Positions:

• chr22-28695855-A-C
• chr22-28695855-A-G
• chr22-28695855-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007194.4(CHEK2):​c.1114T>G​(p.Ser372Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 8.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1114T>G	p.Ser372Ala	missense_variant	11/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1114T>G	p.Ser372Ala	missense_variant	11/15	1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 21, 2021

This sequence change replaces serine with alanine at codon 372 of the CHEK2 protein (p.Ser372Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 20713355). 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"). ClinVar contains an entry for this variant (Variation ID: 479570). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2017

The p.S372A variant (also known as c.1114T>G), located in coding exon 10 of the CHEK2 gene, results from a T to G substitution at nucleotide position 1114. The serine at codon 372 is replaced by alanine, an amino acid with similar properties. This serine is a target of phosphorylation, and a substitution with alanine has been shown in a cell system to be associated with a reduction of kinase response to radiation-induced DNA damage (Guo X et al, J. Biol. Chem. 2010 Oct;285(43):33348-57). This amino acid position is highly 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	0.31
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;.;T;.;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;.;D;.;T;T;D;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.19	N;.;N;.;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;N;N;.;N;D;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.082	T;T;T;.;T;T;.;T;T
Sift4G	Benign	0.10	T;T;T;.;T;T;.;T;T
Polyphen		0.94	P;P;P;.;P;D;P;D;P
Vest4		0.76
MutPred		0.79		Gain of catalytic residue at S372 (P = 0.0223);.;Gain of catalytic residue at S372 (P = 0.0223);.;Gain of catalytic residue at S372 (P = 0.0223);.;Gain of catalytic residue at S372 (P = 0.0223);.;.;
MVP		0.79
MPC		0.15
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.50
gMVP		0.66

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: rs1555913901; hg19: chr22-29091843;