chr22-28711994-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 11P and 2B. PM1PP3PP5_Very_StrongBP4BS2_Supporting

The NM_007194.4(CHEK2):c.707T>C(p.Leu236Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,826 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L236V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:18U:2

Conservation

PhyloP100: 5.68

Publications

18 publications found

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 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 55 uncertain in NM_007194.4

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 22-28711994-A-G is Pathogenic according to our data. Variant chr22-28711994-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 142448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.13351908). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 100 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.707T>C	p.Leu236Pro	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.707T>C	p.Leu236Pro	missense_variant	Exon 6 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000346

AC:

AN:

251368

AF XY:

0.000250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461630

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00224

AC:

100

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000262

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000189

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:18Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4Uncertain:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the CHEK2 protein (p.Leu236Pro). This variant is present in population databases (rs587782471, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a strong personal and family history of breast cancer and other cancers, with nearly 80% of these families reporting Hispanic ancestry. In the Hispanic population, this variant has been observed more frequently among individuals with breast cancer than among controls (OR=3.2, 95% CI [1.5-6.5], p=0.0016), and has been reported as a possible founder mutation (PMID: 25186627, 25318351, 31206626; internal data). ClinVar contains an entry for this variant (Variation ID: 142448). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 37449874). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 14, 2021

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported as disease-causing for hereditary beast cancer [PMID:31206626) -

Oct 03, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 08, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

Mar 29, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2019

Division of Medical Genetics, University of Washington

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

The c.836T>C (p.Leu279Pro) variant has an allele frequency of 0.0003112 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect. In addition, a functional assay in yeast demonstrated decreased growth compared to wild type in yeast transfected with the p.Leu279Pro variant [PMID: 30851065]. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. -

not provided

Pathogenic:4

Feb 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PS3_supporting, PS4 -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.707T>C; p.Leu236Pro variant (rs587782471, ClinVar Variation ID: 142448) is reported in the literature in individuals affected with breast and/or ovarian cancer (selected references: Perez-Ibave 2023, Tung 2015, Weitzel 2019). This variant was found to be enriched in Hispanic BRCA-negative breast cancer patients (OR= 3.2 (1.5-6.5); Weitzel 2019), suggesting this may be a founder variant. Additionally, this variant is found in the Admixed American population with an allele frequency of 0.24% (88/35,436 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.547). However, in vivo yeast based functional analyses and kinase KAP1 and CHK2 assays demonstrate that this variant is damaging (Delimitsou 2019, Stolarova 2023). Based on available information, this variant is considered to be likely pathogenic. References: Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. PÃ©rez-Ibave DC et al. Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico. Genes (Basel). 2023 Jan 28;14(2):341. PMID: 36833268. Stolarova L et al. ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. Clin Cancer Res. 2023 Aug 15;29(16):3037-3050. PMID: 37449874. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Weitzel JN et al. Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer. 2019 Aug 15;125(16):2829-2836. PMID: 31206626. -

Apr 15, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest a damaging effect: decreased DNA damage response in a yeast-based assay, impaired KAP1 phosphorylation and CHEK2 auto-phosphorylation in vitro (PMID: 37449874, 30851065); Observed in individuals with a personal or family history of breast, prostate, and other cancers (PMID: 32885271, 33471991, 25186627, 37145128, 36833268, 35467778, 38748947, 39815370); Case-control studies support this variant is associated with breast cancer, particularly in individuals of Hispanic/Latina ancestry (PMID: 37839337, 31206626, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.836T>C, p.L279P; This variant is associated with the following publications: (PMID: 27621404, 25186627, 31398194, 25318351, 32598223, 33471991, 37145128, 30262796, 31206626, 32885271, 37380563, 36833268, 38091153, 37839337, 38093606, 37449874, 38608781, 38735436, Olivares2023[abstract], 34404389, 30851065, 38748947, 35467778, 19782031, 22419737, 39327123, 38959470, 39815370) -

May 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.707T>C (p.Leu236Pro) variant has been reported in the published literature individuals with breast cancer (PMID: 38091153 (2024), 36833268 (2023), 32885271 (2021), 27621404 (2016), 25186627 (2015), 25318351 (2014)) and prostate cancer (PMID: 35467778 (2022)). Recent studies indicate this variant is statistically associated with breast cancer in the Hispanic population (PMID: 31206626 (2019)). In a yeast based functional study, this variant has been shown to have deleterious effects on CHEK2 DNA damage response (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jun 11, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L236P variant (also known as c.707T>C), located in coding exon 5 of the CHEK2 gene, results from a T to C substitution at nucleotide position 707. The leucine at codon 236 is replaced by proline, an amino acid with similar properties. This alteration was non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648). This alteration was also observed with a statistically increased odds ratio in a cohort of Hispanic breast cancer patients compared to general population control carriers (Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836). Additionally, this variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Based on internal structural assessment, this alteration disrupts the fold of the N-lobe of the kinase domain, near the ATP-binding site (Lountos GT et al. J. Struct. Biol. 2011 Dec;176:292-301). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 10, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces leucine with proline at codon 236 in the kinase domain of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Crystal structure studies on CHEK2 place the reference p.Leu236 in the kinase domain near the ATP binding site and implicate it in mediating CHEK2 dimerization, which is required to form an active kinase (PMID: 16794575, 19782031). Functional studies have shown this variant impairs DNA damage response in yeast (PMID: 30851065) and impairs KAP1 phosphorylation and CHK2 autophosphorylation in complementation assays (PMID: 37449874). In the general population, this variant has been reported exclusively in the Latino population and identified in 88/35436 Latino chromosomes by the Genome Aggregation Database (gnomAD). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 30262796, 33471991). A breast cancer case-control study in the Latino population has shown that this variant is associated with increased breast cancer risk with odds ratio of 3.2 (95% CI, 1.5-6.5; P = .002) (PMID: 31206626). This variant has been observed at an increased frequency in individuals affected with breast cancer than in unaffected individuals (Color internal data). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 04, 2022

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

CHEK2-related cancer predisposition

Pathogenic:2

Jan 06, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2023

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.707T>C (p.Leu236Pro) missense variant has been reported in several individuals with or at elevated risk for primarily breast cancer (PMID: 2531835; 31206626, 32885271, 37145128; DOI:https://doi.org/10.1016/j.clgc.2023.05.012). In a case-control study, p.Leu236Pro was associated with a significantly increased risk of breast cancer risk with an odds ratio of 3.2 (95% CI: 1.5-6.5; p=0.002). It was also reported to have a significant association with estrogen receptor positive tumors (p=0.024) (PMID: 31206626). The highest frequency of this allele in the Genome Aggregation Database is 0.002483 in the Latino/Admixed American population (version 2.1.1), which is higher than expected for a disease-causing variant in this gene. However, it may represent a founder variant in Latin or Indigenous American populations (PMID: 31206626). This variant is in the kinase domain and was shown to impair DNA damage response and growth rate in a yeast-based assay (PMID: 30851065). Based on the collective evidence, the c.707T>C (p.Leu236Pro) variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. -

Familial cancer of breast;C0677776:Hereditary breast ovarian cancer syndrome;C5882668:CHEK2-related cancer predisposition

Pathogenic:1

Jul 17, 2019

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Leu236Pro variant in CHEK2 has been reported in individuals with early onset breast cancer (Yorczyk 2014, Tung 2015, Weitzel 2019). Additionally an in vivo functional study in transformed yeast cells indicates that the Leu236Pro variant are incapable of completing DNA replication and entering mitosis (Delimitsou 2019 -PMID:30851065). Also in our laboratory we have found 9 individuals of Mexican ancestry with breast, ovarian, thyroid and central nervous system tumors and high risk criteria. In summary, the variant meets ACMG criteria to be classified as likely pathogenic. (ACMG criteria: PS3, PM1, PP3, BS2) -

CHEK2-related disorder

Pathogenic:1

Apr 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CHEK2 c.707T>C variant is predicted to result in the amino acid substitution p.Leu236Pro. This variant has been reported to be significantly enriched in females of Hispanic ancestry with breast cancer when compared to controls (OR=2.41, CI=1.87–3.09, p = 5.35×10^12 in Mundt et al. 2023. PubMed ID: 37839337; Weitzel et al. 2019. PubMed ID: 31206626). This variant occurs in the kinase domain of the CHEK2 protein near the ATP binding site (Oliver et al. 2006. PubMed ID: 16794575; Figure 2, Cai et al. 2009. PubMed ID: 19782031; Lountos et al. 2011. PubMed ID: 21963792; Roeb et al. 2012. PubMed ID: 22419737). In addition to breast cancer, this variant has also been reported in an individual with pediatric onset acute lymphoblastic leukemia (Table S4c_TSG, Zhang et al. 2015. PubMed ID: 26580448) and in individuals undergoing hereditary cancer genetic testing (Table 2, Yorczyk et al. 2015. PubMed ID: 25318351; Table 2, Balmaña et al. 2016. PubMed ID: 27621404). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to be damaging (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD and has not been observed in other ancestral populations. This variant has conflicting interpretations of uncertain and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142448). Based on this evidence, we interpret this variant as likely pathogenic. -

Predisposition to cancer

Pathogenic:1

Jun 17, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.707T>C p.(Leu236Pro) missense change is prevalent in the Latino population with a maximum subpopulation frequency of 0.25% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). A case-control study of BRCA-mutation-negative Hispanic women demonstrated that this variant is associated with increased risk of developing breast cancer in this population, suggesting that this may be a founder variant (PMID: 31206626). The in silico tool REVEL is inconclusive about the effect of this variant on protein function, however an in vivo functional study in yeast suggests a deleterious effect (PMID: 30851065). In summary, this variant meets criteria to be classified as likely pathogenic. -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition

Pathogenic:1

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Jun 06, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CHEK2 c.707T>C (p.Leu236Pro) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251368 control chromosomes, predominantly at a frequency of 0.0025 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). However, a relatively recent study performed on a large cohort of Hispanics, reported that the variant is observed more frequently in patients affected with breast cancer than in controls, and the variant was reported as a potential founder mutation in this population (Weitzel_2019). c.707T>C has also been reported in the literature in several individuals (mostly of Hispanic/Latin American origin) affected with HBOC and/or with a positive family/personal history for breast cancer (e.g. Tung_2015, Quezada Urban_2018, SoRelle_2020, Dorling_2021, Chavarri-Guerra_2021, Weitzel_2019, Lerner-Ellis_2021) as well as at least one individual affected with prostate cancer (e.g., Brady_2022). Experimental evidence utilizing an in vivo, yeast-based, functional assay found the variant to restrict growth rate levels to those of the negative control strain carrying the well-known pathogenic CHEK2 variant c.1100delC (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 27621404, 35467778, 30851065, 33471991, 34404389, 30262796, 32598223, 25186627, 31206626, 25318351, 26580448, 32975687). ClinVar contains an entry for this variant (Variation ID: 142448). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

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

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.031

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

0.017

MutationAssessor

Uncertain

2.7

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

PhyloP100

5.7

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.2

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.70

Loss of stability (P = 0.0158);Loss of stability (P = 0.0158);Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;Loss of stability (P = 0.0158);.;.;.;.;

MVP

0.80

MPC

0.18

ClinPred

0.33

GERP RS

5.2

PromoterAI

0.022

Neutral

(source)

Varity_R

0.98

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Other links and lift over