rs1060502713

Variant names:

• chr22-28694081-G-A
• rs1060502713
• NM_007194.4:c.1412C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28694081-G-A
• chr22-28694081-G-C
• chr22-28694081-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007194.4(CHEK2):​c.1412C>T​(p.Pro471Leu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P471S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.00
• Publications: 4 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 45 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1412C>T	p.Pro471Leu	missense_variant	Exon 13 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1412C>T	p.Pro471Leu	missense_variant	Exon 13 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1443816 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718652

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111534

Other (OTH) AF: 0.00 AC: 0 AN: 60088

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 471 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported this variant is functional in a KAP1 kinase assays but had intermediate function in a CHK2 autophosphorylation assay (PMID: 37449874). This variant has been reported in individuals affected with breast and pancreatic cancer (PMID: 31871297, 38476463). 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. -

Oct 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P471L variant (also known as c.1412C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1412. The proline at codon 471 is replaced by leucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with pancreatic cancer (Goldstein JB et al. Clin Cancer Res, 2020 03;26:1385-1394). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial cancer of breast Uncertain:2

Jun 07, 2023

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 471 of the CHEK2 protein (p.Pro471Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 31871297). ClinVar contains an entry for this variant (Variation ID: 410053). 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. -

not provided Uncertain:1

Mar 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with pancreatic cancer (Goldstein et al., 2020); This variant is associated with the following publications: (PMID: 19782031, 22419737, 27320919, 29478780, 31871297, 32906215) -

CHEK2-related cancer predisposition Uncertain:1

May 01, 2023

Department of Genetics, HCU Lozano Blesa

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant summary: CHEK2 c.1412C>T results in the replacement of Pro471 by a Leu residue (p.Pro471Leu). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a woman that developed hormone-responsive breast cancer (BC) at the age of 39 years (luminal-B tumor phenotype). A sister that developed BC at a similar age (41 years) carried also the variant. In the maternal side, four first-degree cousins had died because of BC. Pro471 is located in the kinase domain, appears partly exposed, its buried face is packed onto the residue Arg474 (at the same monomer). Both Pro471 and Arg474 integrate an 8-residue turn (Val468 to Phe475) connecting short α-helices. The turn gets packed against the T-loop (from the second monomer), thus favoring homodimerization. Replacing Pro471 by a leucine residue even if does not bring about a significant steric or chemical change may lead to an increased flexibility in the turn, which could affect the homodimerization of the protein and thus its function. Five reports in ClinVar classify the variant as of Uncertain Significance, while the variant does not appear reported in gnomAD v4 as of now. Other replacements found at this position (P471T and P471S) are also classified by ClinVar as of Uncertain Significance. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) classify Ala392Val as Pathogenic, whereas the AI-based predictor AlphaMissense and the ACMG classification tool Franklin suggests this variant as VUS (Uncertain Significance). Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that Pro471Leu induces conformational unstability on CHEK2 protein. However, Stolarova L. et al’s functional study on KAP1 phosphorylation and CHEK2 autophosphorylation protein capability did not find this variant as functionally impaired (PMID: 37449874). Although the co-segregation and the structural stability analyses could incline us towards proposing a deleterious effect for this variant, the rest of the available evidence is currently insufficient to determine the role of this variant in disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;.;T;.;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;D;.;D;.;D;D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.3	M;.;M;.;M;.;M;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-8.2	D;D;D;.;D;D;.;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;.;D;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;.;D;D;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D
Vest4		0.90
MutPred		0.76		Loss of methylation at K472 (P = 0.0636);.;Loss of methylation at K472 (P = 0.0636);.;Loss of methylation at K472 (P = 0.0636);.;Loss of methylation at K472 (P = 0.0636);.;.;
MVP		0.73
MPC		0.14
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.84
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060502713; hg19: chr22-29090069;