CHEK2

Final classification

VUS

CHEK2 c.1513T>A · p.Ser505Thr

CHEK2

NM_007194.4:c.1513T>A (p.Ser505Thr) is a missense variant in exon 14 of CHEK2, a gene associated with autosomal dominant hereditary breast, ovarian, pancreatic, and prostate cancer predisposition.

Gene

CHEK2

Transcript

NM_007194.4

HGVS · transcript:coding

NM_007194.4:c.1513T>A

Consequence

N/A

GRCh38

chr22:28689164 A>T

GRCh37

chr22:29085152 A>T

Basis Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾

Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

CHEK2 c.1513T>A

NM_007194.4:c.1513T>A (p.Ser505Thr) is a missense variant in exon 14 of CHEK2, a gene associated with autosomal dominant hereditary breast, ovarian, pancreatic, and prostate cancer predisposition.¹ This variant is present at very low frequency in gnomAD: 17/233,642 alleles in v2.1 (AF=0.00728%) and 44/1,595,378 alleles in v4.1 (AF=0.00276%), with the highest subpopulation frequency of 0.083% in East Asians, all below the 0.1% PM2 threshold (PM2_Supporting).² Multiple in silico tools unanimously predict a benign effect: REVEL score 0.018 (benign range), BayesDel score -0.428 (benign range), and SpliceAI max delta 0.00 (no predicted splice impact) (BP4_Supporting).³ PVS1 is not applicable as this is a missense variant, not a null variant. PS1 and PM5 are not applicable as no same-residue pathogenic comparators have been identified. BP7 is not applicable as the variant is not synonymous.⁴ ClinVar consensus is Likely benign from four clinical laboratories, with one additional submitter reporting Uncertain significance and one reporting likely benign. No expert panel classification is available, and no reputable source has classified this variant as pathogenic.⁵ Functional evidence (PS3/BS3) remains unassessed pending full-text review of PMID:30851065 (Delimitsou et al. 2019), which performed functional characterization of CHEK2 variants in a yeast system and may include p.Ser505Thr.⁶ No de novo reports (PS2/PM6), no case-control enrichment data (PS4), no co-segregation data (PP1), and no trans-observation with a pathogenic variant (BP2) are available for this variant. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868) with PM2_Supporting (1 pathogenic point) and BP4_Supporting (1 benign point), the variant is classified as a Variant of Uncertain Significance (VUS), with the benign and pathogenic evidence effectively balancing each other. The CSPEC CHEK2 VCEP v1.0.0 (doc 522546466) did not provide machine-interpretable criteria beyond the raw ruleset.⁷

PM2 + BP4 → VUS

1 cspec ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

4 pvs1_generic_framework ↗

5 clinvar ↗

6 PMID:30851065 ↗

7 generic_acmg_combination_rules

Gene diagram · NM_007194.4 · variants mapped to exon structure

CHEK2 NM_007194.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

44 / 1,595,378

0.0028%

Highest · East Asian

0.078%

Homozygotes

grpmax FAF

0.058%

Allele frequency by ancestry — gnomAD v4.1

observed in 2 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
East Asian	35 / 44,872	0.078%	0
Admixed American	2 / 59,982	0.0033%	0
European (Finnish)	0 / 48,630	—	—
Amish	0 / 912	—	—
Middle Eastern	0 / 4,444	—	—
South Asian	0 / 90,970	—	—
Ashkenazi Jewish	0 / 29,588	—	—
African/African American	0 / 74,830	—	—
European (non-Finnish)	0 / 1,178,980	—	—

“

This variant is present in gnomAD v4.1 (AF= 2.75797e-05; MAF= 0.00276%, 44/1595378 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000779996; MAF= 0.07800%, 35/44872 alleles, homozygotes = 0); grpmax FAF= 0.00057582.

Overall AF

17 / 233,642

0.0073%

Highest · East Asian

0.083%

Homozygotes

grpmax FAF

0.051%

Allele frequency by ancestry — gnomAD v2.1

observed in 2 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
East Asian	15 / 17,996	0.083%	0
Admixed American	2 / 34,358	0.0058%	0
African/African American	0 / 14,722	—	—
Ashkenazi Jewish	0 / 9,866	—	—
European (Finnish)	0 / 11,756	—	—
European (non-Finnish)	0 / 108,668	—	—
Remaining individuals	0 / 5,946	—	—
South Asian	0 / 30,330	—	—

“

This variant is present in gnomAD v2.1 (AF= 7.27609e-05; MAF= 0.00728%, 17/233642 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000833519; MAF= 0.08335%, 15/17996 alleles, homozygotes = 0); grpmax FAF= 0.00051369.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 182441)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.018. BayesDel score = -0.428192.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 24 PMIDs triaged · 8 high-priority

24papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

15942682 ↗ splicing rna

Aberrations of the CHK2 gene are rare in pediatric solid tumors.

In pediatric solid tumors, such as neuroblastoma (NB), it has been reported that the frequency of TP53 gene alterations is lower than that in adult tumors, suggesting that other tumor suppressor genes may play more important roles in the development of pediatric solid tumors. The CHK2 gene, whose product is a checkpoint kinase that plays a central role in DNA damage response and acts upstream of T

BP7PP3PP5PS4PVS1

23918944 ↗ splicing rna

Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.

To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familia

BP7PP3PP5PS4PVS1

25741868 ↗ functional

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PS3PS4

26467025 ↗ functional

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies

BS3PS3PS4

30851065 ↗ functional

Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.

Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Herein, the CHEK2 variant assessm

BS3PP5PS3PS4

32566746 ↗ functional

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome.

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants

BS3PS3PS4

12692171 ↗ case observation

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster exp

PP5PS4

15604628 ↗ case observation

Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PS3PS4

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots