NM_007194.4:c.539G>A

Variant names:

• chr22-28725030-C-T
• rs137853009
• NM_007194.4:c.539G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5 BP4_Moderate

The NM_007194.4(CHEK2):​c.539G>A​(p.Arg180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,908 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:16 B:1
• Conservation: PhyloP100: 1.51

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-28725031-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.22597292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.539G>A	p.Arg180His	missense_variant	Exon 4 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.539G>A	p.Arg180His	missense_variant	Exon 4 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251406 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:16 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:7

Oct 27, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2019

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539G>A variant has been reported in individuals affected with breast cancer, colon cancer, prostate cancer and neuroblastoma (Sodha 2002, Dong 2003, Pugh 2013, Pearlman 2016). The c.539G>A variant has an overall allele frequency of 0.00006 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/), and is more common in African American populations (Lek 2016). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. -

Dec 14, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3_MOD, PM2_SUP, PP3, BP5 -

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 180 of the CHEK2 protein (p.Arg180His). This variant is present in population databases (rs137853009, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer, breast cancer, colorectal cancer, and neuroblastoma (PMID: 12454775, 12533788, 23334666, 27978560, 30086788, 31159747, 32923877). ClinVar contains an entry for this variant (Variation ID: 5596). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16982735, 22114986). 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. -

Sep 08, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R180H variant (also known as c.539G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 539. The arginine at codon 180 is replaced by histidine, an amino acid with highly similar properties. This variant has been identified in individuals diagnosed with breast, prostate, and colorectal cancer (Sodha N et al. Br. J. Cancer. 2002 Dec;87:1445-8; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Greville-Heygate SL et al. JCO Precis Oncol, 2020 May;4:). Functional analyses of the p.R180H allele have supported pathogenicity, with most studies demonstrating low or intermediate levels of functional impairment (Sodha N et al. Cancer Res. 2006 Sep;66:8966-70; Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797; Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119). This amino acid position is well 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. -

Mar 21, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.539G>A (p.Arg180His) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 253624 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.3e-05 vs 0.00031), allowing no conclusion about variant significance. c.539G>A has been reported in the literature in individuals affected with various types of cancers including breast cancer, prostate cancer, colorectal cancer (Desrichard_2011, Dong_2003, Pearlman_2016, Penkert_2018, Sodha_2002, van Puijenbroek_2005, Young_2016, Kleiblova_2019, Tsaousis_2019, Pereira_2022). Functional studies indicate that the variant slightly effects protein expression, stability and kinase activity as measured by activation in response to etoposide induced DNA damage (Sodha_2002). However, this data does not allow convincing conclusions about the variant effect. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.5932G>T, p.Glu1978Ter; CHEK2 c.1100delC, p.Thr367fs), providing supporting evidence for a benign role (Penkert_2018 and Sodha_2002). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of prostate Pathogenic:1

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jan 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with CHEK2-related and other cancers, some of whom had pathogenic variants in other genes (PMID: 12454775, 12533788, 23334666, 27978560, 30086788, 32923877); Published functional studies demonstrate normal phosphorylation in response to DNA damage, but partially reduced protein expression, stability, and kinase activity when compared to wild type (PMID: 16982735, 22114986, 30851065, 31050813); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25629968, 18167186, 21244692, 18085035, 19782031, 15239132, 22385513, 16982735, 12454775, 12533788, 23334666, 22114986, 26787654, 15818573, 27978560, 28055978, 30851065, 30086788, 31050813, 31159747, 22419737, 32923877, 35980532, 36980535, 36983691, 33471991) -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 p.Arg180His variant was identified in 6 of 1998 proband chromosomes (frequency: 0.003) from individuals or families with breast, prostate, neuroblastoma and colorectal cancer and was present in 1 of 846 control chromosomes (frequency: 0.002) from healthy individuals (Sodha 2002, Dong 2003, Pearlman 2017, Pugh 2013, Penkert 2018). The variant was identified in dbSNP (rs137853009) as “with pathogenic, uncertain significance allele”, ClinVar (classified as "uncertain significance by Invitae and 5 others, "pathogenic" by OMIM and "likely benign" by Color). The variant was identified in control databases in 18 of 277,176 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24,028 chromosomes (freq: 0.00008), Latino in 9 of 34,420 chromosomes (freq: 0.0002), European in 7 of 126,672 chromosomes (freq: 0.00006); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In response to DNA damage, cells expressing the p.Arg180His variant resembled wild type by demonstrating normal levels of phosphorylation and proper oligomerization (Sodha 2006). In another study, a recombinant protein expressing the variant reduced kinase activity, but did not completely abolish the protein’s function (Desrichard 2011). Additionally, the p.Arg180His variant co-occurred with pathogenic variants in both the same gene (CHEK2 c.1100delC) and the ATM gene (p.Glu1978X) in breast cancer patients (Sodha 2002, Penkert 2018). The p.Arg180 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 13, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose this criterion: BS3 (strong benign): Kleibova und Stolarova: functional, (Delimitsou 2019: intermed; Sodha 2006: fully activated but reduced expression levels and less stable) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;D;D;.;D;.;.;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;.;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	1.9	L;L;L;L;.;L;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;.
REVEL	Uncertain	0.64
Sift	Benign	0.041	D;D;D;D;T;.;D;D;.
Sift4G	Uncertain	0.031	D;D;D;D;D;.;D;D;D
Polyphen		0.13	B;B;B;B;B;B;B;.;.
Vest4		0.56
MVP		0.92
MPC		0.022
ClinPred		0.12	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.46

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: rs137853009; hg19: chr22-29121018; COSMIC: COSV60417374; COSMIC: COSV60417374;