ClinVar Genomic variation as it relates to human health

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

This rare nonsense variant c.7024C>T, (p.Gln2342Ter) in the BRCA2 gene is rare in public databases (seen once in Gnomad) and is predicted to result in a loss of function of BRCA2. Loss of function variants in BRCA1 are known to be pathogenic for breast cancer. This variant has been observed in multiple unrelated individuals with breast and other cancers (PMID 11836363, 12491487, 19787003). Family history was consistent with mode of iheritance of breast cancer in one family (PMID 19787003). Based upon the above evidence, this c.7024C>T, (p.Gln2342*) variant in BRCA2 is classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Gln2342*) 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 (rs80358928, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19787003, 28637432). ClinVar contains an entry for this variant (Variation ID: 52250). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 14 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with female and male breast cancer (PMID: 12491487, 19787003, 21470549, 25452441, 28637432), including one pedigree that had four breast cancer affected siblings with this variant (PMID: 19787003). This variant has been identified in 1/250660 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.

This sequence change creates a premature translational stop signal (p.Gln2342*) 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 (rs80358928, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19787003, 28637432). ClinVar contains an entry for this variant (Variation ID: 52250). For these reasons, this variant has been classified as Pathogenic.

The p.Q2342* pathogenic mutation (also known as c.7024C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7024. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts, including individuals with male breast and/or prostate cancer (Panchal S et al. Nat Rev Clin Oncol. 2009 Oct;6:604-7; Vesprini D et al. Can Urol Assoc J, 2011 Apr;5:E31-5; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Grindedal EM et al. BMC Cancer. 2017 Jun;17(1):438; Li G et al. J Cancer Res Clin Oncol, 2017 Oct;143:2011-2024; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620; Bernstein-Molho R et al. Breast Cancer Res Treat, 2019 Nov;178:231-237; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Bang YJ et al. Cancer Res Treat, 2021 Oct). Of note, this alteration is also designated 7252C>T and C7252T in the published literature. 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.

Variant summary: BRCA2 c.7024C>T (p.Gln2342X) 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 allele was found at a frequency of 4e-06 in 250660 control chromosomes. c.7024C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (example: Couch_2015, Grindedal_2017, Panchal_2009). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 28637432, 19787003). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.