ClinVar Genomic variation as it relates to human health

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

This sequence change creates a premature translational stop signal (p.Tyr3009Serfs*7) 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 present in population databases (rs80359741, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8589730, 12655574, 22632462, 23479189, 25586199, 26026974). It is commonly reported in individuals of Spanish ancestry (PMID: 8589730, 12655574, 22632462, 23479189, 25586199, 26026974). This variant is also known as 9254del5. ClinVar contains an entry for this variant (Variation ID: 38204). For these reasons, this variant has been 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; Identified in several hereditary breast/ovarian cancer families and has been reported as a founder variant in Northern Spanish populations (Tavtigian 1996, Janaviius 2010, Caputo 2012, de Juan Jimenez 2013, Labidi-Galy 2018, Solano 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9254del5; This variant is associated with the following publications: (PMID: 22632462, 21735045, 24123850, 23479189, 22144684, 8589730, 20033483, 12655574, 18176857, 23683081, 28477318, 29084914, 30720243, 30122538, 30186769, 23199084, 30969264, 26295337, 26026974, 25586199, 32854451, 32039725, 29625052)

Variant summary: BRCA2 c.9026_9030delATCAT (p.Tyr3009SerfsX7) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.9076C>T, p.Gln3026X; c.9093_9094delinsG, p.Thr3033fsX29; c.9097dupA, p.Thr3033fsX11). The variant allele was found at a frequency of 4.1e-06 in 245684 control chromosomes (gnomAD and literature). c.9026_9030delATCAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Serova-Sinilnikova_1997, Neuhausen_1998, Campos_2003, Beristain_2007, Labidi-Galy_2017). 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The BRCA2 c.9026_9030del (p.Tyr3009Serfs*7) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in ZZZZ The frequency of this variant in the general population, 0.000029 (1/34538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

This variant deletes 5 nucleotides in exon 23 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 more than 30 individuals with a personal or family history of breast and/or ovarian cancer and is a recurrent mutation in the Spanish population (PMID: 12655567, 12655574, 12955716, 17262179, 23479189, 23683081, 25586199, 26026974, 28477318, 29084914). This variant has been identified in 1/250686 chromosomes 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.9026_9030del (p.Tyr3009Serfs*7) variant in the BRCA2 gene is located on the exon 23 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Tyr3009Serfs*7), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 30186769, 29084914, 25586199, 23683081, 23479189, 26026974). The variant is reported in ClinVar as pathogenic (ID: 38204) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/250686). Therefore, the c.9026_9030del (p.Tyr3009Serfs*7) variant of BRCA2 has been classified as pathogenic.

The c.9026_9030delATCAT pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 9026 to 9030, causing a translational frameshift with a predicted alternate stop codon (p.Y3009Sfs*7). This pathogenic mutation has been identified in multiple breast and/or ovarian cancer families to date (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Caputo S et al. Nucleic Acids Res. 2012 Jan;40:D992-1002; Blay P et al. BMC Cancer 2013 May;13:243; de Juan I et al. Fam. Cancer 2015 Dec;14:505-13; Gabaldó Barrios X et al. Fam. Cancer 2017 Oct;16(4):477-489), and has been described as a founder mutation of Northeast Spanish origin (de Juan Jiménez I et al. Fam. Cancer 2013 Dec;12:767-77). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.