22-28711986-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4BS2_Supporting

The NM_007194.4(CHEK2):c.715G>A(p.Glu239Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,900 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. E239V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:19O:1

Conservation

PhyloP100: 3.26

Publications

51 publications found

Variant links:

COSMIC-nc: COSV60424940

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

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 44 uncertain in NM_007194.4

BP4

Computational evidence support a benign effect (MetaRNN=0.37750012).

BS2

High AC in GnomAd4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.715G>A	p.Glu239Lys	missense_variant	Exon 6 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.715G>A	p.Glu239Lys	missense_variant	Exon 6 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251364

AF XY:

0.0000810

show subpopulations

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 FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

157

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000116

AC:

129

AN:

1111920

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41532

American (AMR)

AF:

0.000523

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:19Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

Jul 31, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.715G>A (p.Glu239Lys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 32957588 (2020), 30303537 (2019), 27616075 (2017), 27595995 (2016), 26976419 (2016), 26787654 (2016), 25186627 (2015), 21244692 (2011)), prostate cancer (PMIDs: 16941491 (2006), 12533788 (2003)) and colorectal cancer (PMIDs: 33298767 (2021), 28135145 (2017)). This variant has also been identified in reportedly individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 27595995 (2016)). Functional studies showed inconclusive results regarding the variant's impact on protein function (PMIDs: 37449874 (2023), 34903604 (2022), 30851065 (2019), 31050813 (2019), 31780696 (2019), 22419737 (2012), 16835864 (2006)). The frequency of this variant in the general population, 0.00032 (8/25064 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Apr 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies are conflicting: some demonstrate reduced or intermediate kinase activity, stability, and DNA damage response while others report activity similar to wild type (PMID: 16835864, 22419737, 28199314, 30851065, 31780696, 31050813, 34903604, 37449874); Observed in individuals with a history of breast, prostate, colorectal, thyroid, or other cancers (PMID: 12533788, 21244692, 26506619, 27616075, 26976419, 28135145, 31780696, 30303537, 32923877, 33471991, 33692755, 35264596, 36315513, 36468172, 31614935, 32191290, 35534704, 38061684); Case control studies suggest this variant is not associated with breast, ovarian, or prostate cancer (PMID: 27595995, 37449874); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.844G>A, p.E282K; This variant is associated with the following publications: (PMID: 12533788, 21244692, 25318351, 16835864, 22419737, 23298314, 25525159, 16941491, 26506619, 26976419, 26787654, 28135136, 28135137, 27616075, 28199314, 28135145, 31050813, 30851065, 31780696, 32957588, 34426522, 33309985, 33692755, 32923877, 35264596, 33471991, 36315513, 34903604, 30303537, 36468172, 32191290, 37449874, 27595995, 31614935, 35451682, 37732318, 38007399, 35534704, 38441358, 38476463, 19782031, 38061684, 37306523, 39174791) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2: PS3:Supporting -

Apr 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2: p.Glu239Lys variant (rs121908702) has been reported in association with colorectal, prostate, breast, and ovarian cancers, including control groups (Yurgelun 2017, Kraus 2017, Dong 2003, and Southey 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Finnish population (identified on 8 out of 25,726 chromosomes) and has been reported to the ClinVar database (Variation ID: 5600). Reconstitution of this variant in yeast cells lacking CHEK2 showed a â€œmoderateâ€ decrease of growth compared to WT after DNA damage induction by methyl methanesulfonate (Roeb 2012). This variant is moderately conserved in the kinase domain of the CHEK2 protein and has been shown to reduce the phosphorylation activity of the enzyme with model substrate (Wu 2006); however computational predictors indicate a neutral effect on protein structure and function (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu239Lys variant with certainty. -

Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Familial cancer of breast

Pathogenic:1Uncertain:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the CHEK2 protein (p.Glu239Lys). This variant is present in population databases (rs121908702, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, non-medullary thyroid cancer, and/or breast cancer (PMID: 12533788, 21244692, 26506619, 26787654, 26976419, 27595995, 27616075, 28135145, 30303537, 31614935, 32957588, 33692755, 36468172). ClinVar contains an entry for this variant (Variation ID: 5600). 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: 16835864, 22419737, 30851065, 34903604). 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. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic based on an internal history weighting algorithm that has been validated and shown to have greater than 99.5% positive and negative predictive values [PMID: 25085752]. The algorithm shows this variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in CHEK2. Curve available upon request. -

Mar 24, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 17, 2025

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.715G>A (p.Glu239Lys) results in a conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 0.00011 in 1613900 control chromosomes, predominantly at a frequency of 0.00033 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.056 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). This variant was also observed in the heterozygous state in 2 individuals with no personal history of cancer who are >70 years of age (FLOSSIES database). c.715G>A has been reported in the literature in numerous individuals affected with CHEK2-related conditions, without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with CHEK2-related conditions. In a multicenter large case-control study, this variant failed to confer any statistically-significant association with breast, ovarian, and prostate cancers (Southey_2016). Pathogenic variants in CHEK2 gene constitute risk alleles that confer low risk for breast cancer (e.g. CHEK2 1100delC). Therefore, this variant shows some features of a high-prevalence mild/intermediate risk allele, however the current data to support this are weak. Functional studies suggest this variant has an intermediate effect in yeast-based in vivo DNA damage response and was found to partially reduce CHEK2 kinase activity in vitro (Wu_2006, Roeb_2012, Dutil_2019), however data were not robust. The following publications have been ascertained in the context of this evaluation (PMID: 12533788, 26506619, 27616075, 21244692, 29659569, 22419737, 27595995, 25186627, 16835864, 25318351, 26787654, 28135145, 26580448, 31780696). ClinVar contains an entry for this variant (Variation ID: 5600). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Aug 11, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E239K variant (also known as c.715G>A), located in coding exon 5 of the CHEK2 gene, results from a G to A substitution at nucleotide position 715. The glutamic acid at codon 239 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in cohorts of prostate cancer patients, unselected non-Hodgkin lymphoma patients, and BRCA-negative HBOC patients (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Havranek O et al. PLoS ONE 2015 Oct;10(10):e0140819; Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). In two large case-control studies, p.E239K was detected in breast cancer patients but not in healthy controls; however, these studies did not have enough carriers to demonstrate statistically increased odds (Girard E et al. Int J Cancer. 2019 04;144:1962-1974; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In contrast, another case-control study identified p.E239K in 2/3360 healthy controls but not in 1928 breast cancer cases (Klieblova P et al. Int. J. Cancer. 2019 Oct;145(7):1782-1797). In another large study, this variant was reported in 18/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439) and in the combined case-control data in the ENIGMA CHEK2gether Project, this variant was reported in 15/73048 cases and 10/88658 controls, with insignificant OR of 1.63 (95% CI 0.68-4.06), p=0.24 (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Multiple functional studies have found that this alteration demonstrates partially reduced CHK2 kinase activity (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Klieblova P et al. Int. J. Cancer 2019 Oct;145(7):1782-1797; Boonen RACM et al. Cancer Res, 2022 02;82:615-631). However, in other studies, this variant was considered functional (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). 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. -

Feb 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with lysine at codon 239 in the kinase domain of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to exhibit partially reduced protein expression levels (PMID: 33606978), CHEK2 kinase activity (PMID: 16835864, 31050813, 31780696, 34903604, 37449874) and DNA damage response (PMID: 22419737), but normal function in yeast complementation assay (PMID: 30851065). This variant has been observed in individuals affected with breast cancer (PMID: 21244692, 26976419, 27616075, 31780696, 32957588), colorectal cancer (PMID: 28135145), non-Hodgkin lymphoma (PMID: 26506619), prostate cancer (PMID: 12533788), papillary thyroid cancer (PMID: 33692755), and pheochromocytoma (PMID: 34630562). In large breast cancer case-control studies, this variant has not shown a conclusive association with increased risk of breast cancer (OR = 1.70, 95% CI 0.73 to 3.93, p=0.210 in PMID: 27595995; OR = 2.274, 95% CI 0.95 to 5.445, p=0.071 in PMID: 33471991). In addition, this variant has not shown significant association with ovarian cancer or prostate cancer in a large case-control study (PMID: 27595995). This variant has been identified in 24/282754 chromosomes 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. -

CHEK2-related cancer predisposition

Uncertain:2

Jun 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS3_MOD,PS4_MOD,PM5_SUP -

Dec 09, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHEK2-related disorder

Uncertain:1

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CHEK2 c.715G>A variant is predicted to result in the amino acid substitution p.Glu239Lys. This variant has been documented in individuals with prostate cancer (Dong et al. 2003. PubMed ID: 12533788; Wu et al. 2006. PubMed ID: 16835864), breast cancer (Roeb et al. 2012. PubMed ID: 22419737) and ductal carcinoma in situ (Kraus et al. 2017, Supplemental Table 4. PubMed ID: 27616075). This variant has been reported to have a negative association with breast, prostate, and ovarian cancers among Europeans (Southey et al. 2016. PubMed ID: 27595995). Functional studies on this variant have indicated its possible role in altered acetylation (Suo et al. 2013. PubMed ID: 23298314), partially reduced kinase activity (Wu et al. 2006. PubMed ID: 16835864), and DNA damage response (Roeb et al. 2012. PubMed ID: 22419737). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5600/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Prostate cancer

Uncertain:1

Feb 01, 2003

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Predisposition to cancer

Uncertain:1

Apr 14, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.715G>A (p.Glu239Lys) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive and functional assays are not in agreement about the effect of this variant on protein function (PMID: 16835864, 22419737, 30851065, 31050813, 31780696, 34903604). This variant has been reported individuals with breast cancer (21244692, 27616075, 30303537) and prostate cancer (PMID: 12533788, 16835864). It is present 2x in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;.;T;.;T;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.73

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.38

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.36

N;N;N;.;N;.;N;.;N;.;.;.;.

PhyloP100

3.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;N;N;.;N;N;.;N;N;N;.;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.17

T;T;T;.;T;T;.;T;T;T;.;T;T

Sift4G

Benign

0.26

T;T;T;.;T;T;.;T;T;T;.;.;D

Polyphen

0.98

D;P;D;.;D;D;D;D;P;.;.;.;.

Vest4

0.85

MVP

0.93

MPC

0.039

ClinPred

0.13

GERP RS

5.3

PromoterAI

-0.068

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.69

gMVP

0.76

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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