ClinVar Genomic variation as it relates to human health

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

The frame shift c.7251_7252del(p.His2417GlnfsTer3) variant has been reported previously in patients affected with {Breast-ovarian cancer, familial, 2} (Lubinski et. al., 2004). The p.His2417GlnfsTer3 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Histidine 2417, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.His2417GlnfsTer3. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 26843898 (2016)) as well as other cancers (PMID: 15131399 (2004), 29753700 (2018)). Based on the available information, this variant is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.His2417Glnfs*3) 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 breast, ovarian, and possibly other cancers (PMID: 15131399). ClinVar contains an entry for this variant (Variation ID: 52298). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 2 nucleotides in exon 14 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 is also known as 7479delCA, c.7249delCA, and c.7249_7250delCA in the literature. This variant has been reported in individuals affected with breast cancer, and in high-risk hereditary breast and ovarian cancer families (PMID: 15131399, 25330149, 25948282, 31209999). This variant has also been identified in two families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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.

Variant summary: BRCA2 c.7251_7252delCA (p.His2417GlnfsX3) 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. The variant was absent in 251262 control chromosomes. c.7251_7252delCA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Kluska_2015,Rebbeck_2018). These data indicate that the variant is 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.

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Lubinski 2004, Cybulski 2014, Kluska 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as BRCA2 7479_7480del, 7479delCA, 7249delCA, and 7249_7250delCA; This variant is associated with the following publications: (PMID: 15131399, 27225819, 24784157, 26843898, 25330149, 25948282, 29753700, 30787465)

The c.7251_7252delCA pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7251 to 7252, causing a translational frameshift with a predicted alternate stop codon (p.H2417Qfs*3). This alteration has been identified in individuals with hereditary breast and/or ovarian cancer (Lubinski J, Fam. Cancer 2004; 3(1):1-10; Kluska A et al. BMC Med Genomics 2015 May;8:19; Cybulski C et al. Clin. Genet. 2015 Oct;88(4):366-70). Of note, this alteration is also designated as 7479delCA and c.7249delCA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.