rs137853011

Variant names:

• chr22-28695219-G-A
• rs137853011
• NM_007194.4:c.1283C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28695219-G-A
• chr22-28695219-G-C
• chr22-28695219-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_007194.4(CHEK2):​c.1283C>T​(p.Ser428Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,610,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002070845: Functional studies show p.Ser428Phe disrupts the function of the CHEK2 protein (PMIDs: 15649950, 22419737)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S428P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:38 U:1 O:1
• Conservation: PhyloP100: 3.46
• Publications: 119 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, ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

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

  Inheritance: Unknown 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 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002070845: Functional studies show p.Ser428Phe disrupts the function of the CHEK2 protein (PMIDs: 15649950, 22419737); SCV000292126: Functional studies have shown that the mutant protein is partially defective in DNA damage repair function (PMID: 15649950, 18571837, 22419737), but a complementation assay in human cells showed this variant did not impact KAP1 phosphorylation or CHEK2 autophosphorylation (PMID: 37449874).; SCV000821728: experimental studies in yeast have shown that this variant disrupts CHEK2 protein function (PMID: 15649950, 22419737).; SCV000253983: Experimental studies in yeast have shown that the Ser428Phe substitution abrogates CHEK2 protein function to a similar extent as other partially damaging alleles (PMID: 15649950, 22419737).; SCV000839938: Functional assays in yeast showed that the mutant allele disrupt the the normal function of CHEK2 [PMID 15649950].; SCV000149903: Published functional studies demonstrate a damaging effect: loss of CHEK2-mediated DNA damage response and impaired protein function in yeast complementation assays (Shaag et al., 2005; Tischkowitz et al., 2008; Roeb et al., 2012); SCV000437715: Functional studies in yeast based on a lack of complementation of RAD53 demonstrated that the variant abrogates CHEK2 function (Shaag et al. 2005; Tischkowitz et al. 2008; Roeb et al. 2012).; SCV000698769: "In functional studies by multiple independent research groups this variant showed a reduced ability to complement the lethality of a Rad53 deletion in S. cerevisiae (Shaag_2005, Tischkowitz_2008, Roeb_2012, Yilmaz_2014)."; SCV001549025: Functional studies revealed this variant to have loss of CHEK2-mediated DNA damage response (Roeb 2012) and to impair protein function in yeast complementation assays (Shaag 2005, Tischkowitz 2008); however, these studies are not considered sufficient evidence of pathogenicity because of the known variability of yeast assays for CHEK2 (Mundt 2017). Roeb 2012; SCV001653110: In vivo functional studies in yeast support an impact on protein function (Shaag 2005 PMID: 15649950, Roeb 2012 PMID: 22419737).; SCV004752724: "In addition, this variant was shown to abrogate CHEK2 function in yeast complementation assays (Shaaq et al. 2005. PubMed ID: 15649950; Roeb et al. 2012. PubMed ID: 22419737)."; SCV000914987: Functional studies in yeast based on a lack of complementation of RAD53 demonstrated that the variant abrogates CHEK2 function (Shaag et al. 2005; Tischkowitz et al. 2008; Roeb et al. 2012).; SCV006557194: Experimental studies in yeast have shown that this substitution abrogates CHEK2 protein function.
• PP5: Variant 22-28695219-G-A is Pathogenic according to our data. Variant chr22-28695219-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5603.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013116658). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.1283C>T	p.Ser428Phe	missense	Exon 12 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1412C>T	p.Ser471Phe	missense	Exon 13 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1376C>T	p.Ser459Phe	missense	Exon 13 of 16	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1283C>T	p.Ser428Phe	missense	Exon 12 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1412C>T	p.Ser471Phe	missense	Exon 13 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.1082C>T	p.Ser361Phe	missense	Exon 10 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000486 AC: 122 AN: 250800 AF XY: 0.000457

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1457954 Hom.: 3 Cov.: 29 AF XY: 0.000273 AC XY: 198 AN XY: 725584

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000722 AC: 80 AN: 1108578

Other (OTH) AF: 0.000664 AC: 40 AN: 60228

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000227 Hom.: 1

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
8	-	-	Familial cancer of breast (8)
5	-	-	Hereditary cancer-predisposing syndrome (7)
2	-	-	CHEK2-related cancer predisposition (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer, susceptibility to (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast cancer, susceptibility to (1)
1	-	-	Breast neoplasm (1)
1	-	-	CHEK2-related cancer risk (1)
1	-	-	CHEK2-related disorder (1)
1	-	-	Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition (1)
-	1	-	Inherited breast cancer and ovarian cancer (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.028	D
Polyphen		0.91	P
Vest4		0.68
MVP		0.77
MPC		0.16
ClinPred		0.14	T
GERP RS		5.8
Varity_R		0.67
gMVP		0.60
Mutation Taster		=68/32	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs137853011; hg19: chr22-29091207; COSMIC: COSV60415349; COSMIC: COSV60415349;