rs1060502713

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.00

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 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/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1412C>T	p.Pro471Leu	missense_variant	13/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1412C>T	p.Pro471Leu	missense_variant	13/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1443816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718652

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jun 07, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 14, 2019	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 (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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	Jul 25, 2022	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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Genetics, HCU Lozano Blesa

May 01, 2023

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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2023

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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

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

LIST_S2

Uncertain

0.92

.;D;.;D;.;D;D;D;.

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.3

M;.;M;.;M;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

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

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over