rs1555915348

Variant names:

• chr22-28699852-G-A
• rs1555915348
• NM_007194.4:c.994C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28699852-G-A
• chr22-28699852-G-C
• chr22-28699852-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007194.4(CHEK2):​c.994C>T​(p.Leu332Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L332V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.46
• Publications: 1 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.994C>T	p.Leu332Phe	missense_variant	Exon 9 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.994C>T	p.Leu332Phe	missense_variant	Exon 9 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460690 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726760

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110924

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Jul 29, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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"). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 647008). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 332 of the CHEK2 protein (p.Leu332Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 25, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L332F variant (also known as c.994C>T), located in coding exon 8 of the CHEK2 gene, results from a C to T substitution at nucleotide position 994. The leucine at codon 332 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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	0.73
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;.;D;.;D;D;D;.;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.0	M;M;M;.;M;.;M;.;M;.;.;.
PhyloP100		5.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;D;D;.;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D;D;D;.;D;T;.;T;D;D;.;D
Sift4G	Uncertain	0.023	D;D;D;.;D;D;.;D;D;D;.;.
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;.;.
Vest4		0.80
MutPred		0.68		Gain of catalytic residue at M331 (P = 0.1169);Gain of catalytic residue at M331 (P = 0.1169);Gain of catalytic residue at M331 (P = 0.1169);.;Gain of catalytic residue at M331 (P = 0.1169);.;Gain of catalytic residue at M331 (P = 0.1169);.;Gain of catalytic residue at M331 (P = 0.1169);.;.;.;
MVP		0.78
MPC		0.16
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.65
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs1555915348; hg19: chr22-29095840;