Evidence collected from Nucleati Germline Cancer Evidence Base for variants presented at ACMG 2023 meeting.

The American College of Medical Genetics and Genomics (ACMG) is a professional organization with a vision to advance the practice of medical genetics and genomics by providing guidance and resources for genetic testing, counseling, and research. The ACMG also promotes education and awareness of genetics's importance in healthcare and advocates for the ethical and responsible use of genetic information. The ACMG Annual Meeting is a significant event that brings together experts worldwide to share knowledge, discuss advancements, and offer presentations, workshops, and networking opportunities for professionals in various specialties. The abstracts presented at the meetings are available free of charge to the community.

In this article, we demonstrate the utility of Nucleati Germline Cancer Evidence base in a real-world scenario where a variant has been found from typical sequencing or panel assay and published evidence in the form of case reports, case series, or GWAS studies may help to strengthen the association with patient's phenotype. First, we collected 54 abstracts presented under the "Cancer Genetics and Therapeutics" category from the Genetics in Medicine ACMG 2023 meeting supplement. Next, we manually collected information about genes and variants. Out of 54 abstracts, 16 articles mention genes and variants in the abstract. We used this information to search Nucleati Germline Cancer Evidence Base. Table 1 summarizes the retrieved case reports, case series data, and GWAS studies identified from Nucleati Germline Cancer Evidence Base.

Table 1: Title and Variations identified from published abstracts corresponding evidence collected from Nucleati Germelin Cancer Evidence Base.

Title Variation Evidence
Case Reports Case Series GWAS
Mosaic Li-Fraumeni syndrome identified in patient with a previously presumed germline variant following preimplantation genetic testing: A case report TP53:c.733G>A(p.Gly245Ser) Report (3) Series (3) -
Spectrum of genetic alterations for hereditary paraganglioma-pheochromocytoma syndrome testing: Eight-year experience from a single diagnostic laboratory SDHD:c.242C>T(p.Pro81Leu) Report (7) Series (30) -
Spectrum of genetic alterations for hereditary paraganglioma-pheochromocytoma syndrome testing: Eight-year experience from a single diagnostic laboratory SDHB:c.268C>T(p.Arg90Ter) Report (4) Series (20) -
Spectrum of genetic alterations for hereditary paraganglioma-pheochromocytoma syndrome testing: Eight-year experience from a single diagnostic laboratory SDHB:c.725G>A(p.Arg242His) Report (1) Series (18) -
Cascade testing with comprehensive multigene panels for hereditary cancer identifies unexpected findings in relatives APC:p.Ile1307Lys(p.Ile1307Lys) Report (6) Series (46) GWAS (1)
Defining the pleiotropic GATA2 deficiency phenotype for the development of ACMG-AMP variant curation rules for GATA2* GATA2:c.1061C>T(p.Thr354Met) Report (2) Series (7) -
Identification of novel variant in WT1 gene in African-American girl with Denys-Drash syndrome WT1:c.1053dup(p.Pro352Alafs) - - -
Discrepant germline genetic testing for inherited bone marrow failure syndrome in a patient with myelodysplastic syndrome STK4:c.47A>G(p.Lys16Arg) - - -
Discrepant germline genetic testing for inherited bone marrow failure syndrome in a patient with myelodysplastic syndrome RTEL1:c.932C>(p.Thr311Ile) - - -
Discrepant germline genetic testing for inherited bone marrow failure syndrome in a patient with myelodysplastic syndrome SRP72:c.18C>G(p.Ser6Arg) - - -
Germline variants in genes associated with parkinsonism in cancer patients: A case report PRKN:c.155delA(p.Asn52Metfs) - Series (1) -
Reanalysis of intronic variants reveals novel likely pathogenic DICER1 splice variant in pleuropulmonary blastoma proband DICER1:c.574-26T>C(c.574-26T>C) - - -
Evaluation of PMS2 gene variant c.2182_2184delinsG by NGS in a Brazilian sample: How long-range PCR can solve homology? PMS2:c.2182_2184delinsG(p.Thr728Alafs) - Series (1) -
Novel frameshift MLH1 germline mutation in a Moroccan Lynch syndrome family MLH1:c.910dupG(c.910dupG) Report (1) Series (1) -
Incidental findings in FH and SDHA genes: Navigating cancer risk assessment and follow-up recommendations FH:c.521C>G(c.521C>G) - Series (1) -
Development and validation of an NGS assay for the detection of clinically actionable genetic variants in DPYD and UGT1A1 DPYD:c.557A>G(c.557A>G) - - -
Development and validation of an NGS assay for the detection of clinically actionable genetic variants in DPYD and UGT1A1 DPYD:c.2846A>T(c.2846A>T) Report (2) Series (5) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.1100delC(p.Thr367fs) Report (6) Series (152) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.470T>C(p.Ile157Thr) Report (3) Series (78) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:1427C>T(p.Thr476Met) Report (2) Series (19) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.470T>C(p.Ile157Thr) Report (3) Series (78) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.1100delC(p.Thr367fs) Report (6) Series (152) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.1427C>T(p.Thr476Met) Report (2) Series (19) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.349A>G(p.Arg117Gly) Report (1) Series (22) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.1263delT(p.Ser422fs) - Series (5) -
Risk of cancer from 6 common germline variants in CHEK2: A genome-first approach to the Geisinger and UK Biobank cohorts* CHEK2:c.1283C>T(p.Ser428Phe) - Series (14) -
Identification of PALB2 variants and associated cancers in a large, unselected healthcare population BRCA1:c.3756_3759delGTCT(c.3756_3759delGTCT) Report (1) Series (1) -
Identification of PALB2 variants and associated cancers in a large, unselected healthcare population PMS1:c.2647C>T(c.2647C>T) - - -
Identification of PALB2 variants and associated cancers in a large, unselected healthcare population APC:c.6579del(c.6579del) - - -
The status of germline variants of unknown significance in minorities: Middle Eastern patients with HBOC* BRCA1:c.2217delA(c.2217delA) - - -
The status of germline variants of unknown significance in minorities: Middle Eastern patients with HBOC* BRCA2:c.8377G>A(c.8377G>A) - Series (3) -
The status of germline variants of unknown significance in minorities: Middle Eastern patients with HBOC* CHEK2:c.592+3A>T(c.592+3A>T) - Series (4) -
Variant overlooked: A partial deficiency TP53 allele that skirts interpretation criteria TP53:c.590T>A(p.Val197Glu) - - -
Variant overlooked: A partial deficiency TP53 allele that skirts interpretation criteria TP53:c.590T>G(p.Val197Gly) - - -
Variant overlooked: A partial deficiency TP53 allele that skirts interpretation criteria TP53:p.Val197Met(p.Val197Met) - Series (2) -

Results

The results showed that the Nucleati Germline Cancer Evidence Base provided at least one piece of evidence for 23 out of 35 genetic variants reported in 16 abstracts. This finding suggests that the database is a valuable resource for clinicians and researchers seeking information on genetic variants associated with hereditary cancer.

The median number of articles available for each variant in the Germline Cancer Evidence Base was 3, with a range of 0 to 163 articles. This wide range indicates that the variable frequency with which variant reported in the literatures. It also shows the extent of data available in the Nucleati Germline Cancer Evidence Base.

Among the variants with available evidence in the database, 16 had at least one case report article, providing information on the clinical characteristics and outcomes of individual patients with the variant. Additionally, 24 had at least one case series article, describing the clinical characteristics and outcomes of a group of patients with the variant. Finally, 5 had at least one GWAS article, which examined the association between the variant and the risk of developing cancer in large populations.

Conclusions

In summary, the study demonstrated the usefulness of the Nucleati Germline Cancer Evidence Base as a valuable resource for clinicians and researchers seeking information on genetic variants associated with cancer. The database provides information on the clinical characteristics and outcomes of patients with the variants and their association with the risk of developing cancer, making it an essential tool for advancing cancer research and treatment.