ClinVar Genomic variation as it relates to human health

Variant allele predicted to encode a truncated non-functional protein.

Variant summary: BRCA2 c.4936_4939delGAAA (p.Glu1646GlnfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 238878 control chromosomes (gnomAD). c.4936_4939delGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Finkelman_2012, Infante_2006, Kaufman_2006, Krajc_2008, Borg_2010, Beristain_2010, de Juan Jimenez_2012, Novakovic_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a pathogenic BRCA2 variant on the opposite allele (in trans) in siblings with Fanconi anemia (Wagner 2004); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Kaufman 2006, Stegel 2011, Novakovic 2012, de Juan Jimenez 2013, de Juan 2015, Hoberg-Vetti 2015, Bunnell 2016, Bannon 2018); Also known as c.5164del4; This variant is associated with the following publications: (PMID: 24301060, 22430266, 27276934, 28127413, 30274973, 30293905, 21232165, 23479189, 15070707, 22923021, 26350514, 15689453, 26026974, 26656232, 20104584, 26681312, 16758124, 20033483, 16825431, 17020472, 27741520, 27160020, 28503720, 28637432, 29560538, 28477318, 29084914, 28152038, 29086229, 30014164, 30755392, 30720863, 30322717, 31159747)

The p.Glu1646fs variant in BRCA2 has been reported as heterozygous in >20 indivi duals with BRCA2-associated cancers and as compound heterozygous in 2 siblings w ith Fanconi anemia (H?berg-Vetti 2016, Jimenez 2013, Stegel 2011, Wagner 2004, B reast Cancer Information Core (BIC) database). It was absent from large populati on studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 1646 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the BR CA2 gene is an established disease mechanism in individuals with hereditary brea st and ovarian cancer (HBOC). In addition, this variant was classified as Pathog enic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar S CV000300803.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner .

This sequence change deletes 4 bases from exon 11 of the BRCA2 mRNA (c.4936_4939delGAAA), causing a frameshift after codon 1646. This creates a premature translational stop signal 23 amino acid residues later (p.(Glu1646Glnfs*23) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant is also known in the literature as c.4933_4936delAAAG and 5164del4 and has been described in the literature in families with breast and/or ovarian cancer and Fanconi anemia (PMID: 23479189, 22923021, 15070707,31159747). The mutation database Clinvar contains entries for this variant (Variation ID:37935).

The BRCA2 c.4936_4939delGAAA; p.Glu1646GlnfsTer23 variant (rs80359473, also known as 5164del4), is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer and Fanconi anemia (de Juan 2015, de Juan Jimenez 2013, Esteban Cardenosa 2010, Gabaldo Barrios 2017, Infante 2006, Labidi-Galy 2018, Rummel 2017, Schayek 2018, Wagner 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37935) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. de Juan Jimenez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013 Dec;12(4):767-77. Esteban Cardenosa E et al. Broad BRCA1 and BRCA2 mutational spectrum and high incidence of recurrent and novel mutations in the eastern Spain population. Breast Cancer Res Treat. 2010 May;121(1):257-60. Gabaldo Barrios X et al. Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. Fam Cancer. 2017 Oct;16(4):477-489. Infante M et al. High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-León (central Spain). J Hum Genet. 2006;51(7):611-7. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. Rummel SK et al. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):593-601. Schayek H et al. Mutational analysis of candidate genes in Israeli male breast cancer cases. Breast Cancer Res Treat. 2018 Jul;170(2):399-404. Wagner JE et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood. 2004 Apr 15;103(8):3226-9.

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in breast, ovarian, male breast and pancreatic cancer in the published literature (PMID: 30274973 (2018), 26026974 (2015), 22923021 (2012), 21232165 (2011), 17020472 (2006), 16030099 (2005)). This variant has also been reported in Fanconi Anemia patients (PMID: 15070707 (2004)). Based on the available information, this variant is classified as pathogenic.

This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 heterozygous individuals affected with breast and ovarian cancer (PMID: 16030099, 17020472, 20104584, 21553119, 23479189, 26026974, 28503720, 29084914, 29560538, 33471991; Leiden Open Variation Database DB-ID BRCA2_001062, 34290354, 34645131, 34933735, Color internal data) and 3 individuals affected with pancreatic cancer (PMID: 30274973, Color internal data). This variant also has been observed in compound heterozygous state with a known pathogenic BRCA2 mutation in individuals affected with the recessive disease, Fanconi anemia (PMID: 15070707). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Glu1646Glnfs*23) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 15070707, 20960228, 22923021, 23479189, 26350514). This variant is also known as c.4933_4936delAAAG and 5164del4. ClinVar contains an entry for this variant (Variation ID: 37935). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 heterozygous individuals affected with breast and ovarian cancer (PMID: 16030099, 17020472, 20104584, 21553119, 23479189, 26026974, 28503720, 29084914, 29560538, 33471991; Leiden Open Variation Database DB-ID BRCA2_001062, 34290354, 34645131, 34933735, Color internal data) and 3 individuals affected with pancreatic cancer (PMID: 30274973, Color internal data). This variant also has been observed in compound heterozygous state with a known pathogenic BRCA2 mutation in individuals affected with the recessive disease, Fanconi anemia (PMID: 15070707). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The c.4936_4939delGAAA (p.E1646Qfs*23) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 4 nucleotides from position 4936 to 4939, causing a translational frameshift with a predicted alternate stop codon after 23 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Weitzel, 2005; Kaufman, 2006; Infante, 2006; Borg, 2010; Stegel, 2011; Laitman, 2011; De Leeneer, 2012; Novakovi, 2012; de Juan Jiménez, 2013; Høberg-Vetti, 2016; Gabaldó Barrios, 2017; Bunnell, 2017; Baert, 2017; Rummel, 2017; Carter, 2018; Labidi-Galy, 2018; Deng, 2019; Palmer, 2020; Breast Cancer Association, 2021). This mutation has also been reported in a patient with early-onset pancreatic cancer (Bannon, 2018), as well as a male patient with transitional cell carcinoma (Kinget, 2021). Of note, this alteration is also designated as 5164del4, c.5164_5167del, and c.5164_5167delGAAA in published literature. Based on the available evidence, this alteration is classified as pathogenic.