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.Ser1955*) 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 (rs80358815, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11802209, 15131399, 16683254, 24504028, 24728189, 26483394, 26586665, 27433846). This variant is also known as 6092C>A. ClinVar contains an entry for this variant (Variation ID: 51954). For these reasons, this variant has been classified as Pathogenic.

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

Nonsense 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Meindl et al., 2002; Lubinski et al., 2004; Cunningham et al., 2014; Pritchard et al., 2016; Barnes et al., 2018); Also known as 6092C>A; This variant is associated with the following publications: (PMID: 27433846, 11802209, 30787465, 26483394, 24504028, 15131399, 19340607, 26848529, 24728189, 25525159, 27393621, 28324225, 12928470, 26295337, 26586665, 16683254, 29101607, 28476184, 29446198, 30720243, 30702160, 29625052, 26689913, 31825140, 36149077, 32073954, 29922827)

Variant summary: BRCA2 c.5864C>A (p.Ser1955X) 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 1.2e-05 in 250960 control chromosomes (gnomAD). c.5864C>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (e.g. Meindl_2002, de la Hoya_2003, Lubinski_2004, Song_2014, Dorling_2021), and the variant was found to co-segregate with the disease in multiple HBOC families. 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: 11802209, 15131399, 24728189, 12928470, 33471991). 16 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

PP5, PM2, PS4_moderate, PVS1

This variant changes 1 nucleotide in exon 11 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 at least five individuals affected with breast, ovarian, pancreatic and prostate cancer and two unaffected individuals (PMID: 19340607, 24504028, 26483394, 27433846, 33471991; Leiden Open Variation Database DB-ID BRCA2_001762). This variant also has been reported in suspected hereditary breast and ovarian cancer families (PMID: 11802209, 12928470, 15131399, 16683254, 28324225). This variant has been identified in 4/282358 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 p.S1955* pathogenic mutation (also known as c.5864C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 5864. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in multiple high-risk breast and/or ovarian cancer kindreds (Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). It has also been reported in a patient with epithelial ovarian cancer and a patient with metastatic prostate cancer, both of whom were unselected for family history of cancer or age at diagnosis (Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53). Of note, this alteration is also designated as S1955X and 6092C>A in 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.

BRCA2: PVS1, PM2, PP1, PS4:Supporting

ACMG Criteria: PVS1, PS4, PM2, PP1, PP4, PP5; Variant found in a heterozygous state

The BRCA2 p.Ser1955X variant was identified in 3 of 4656 proband chromosomes (frequency: 0.001) from German and multiethnic cohorts of individuals or families with ovarian and breast/other cancers (Meindl 2002, Lubinski 2004). In a study correlating mutation locus to disease risk in BRCA2 positive patients, Lubinski (2004) found that mutations falling within BIC 3035-6629, considered the OCCR (ovarian cancer cluster region), had increased risk of ovarian cancer and decreased risk of breast and prostate cancers compared to nonOCCR regions. In another study assessing HRD (homologous recombination deficiency) in ovarian cancer patients unselected for family history, it was found that patients with germline or somatic mutations in BRCA1, BRCA2 or RAD51C, were likely to have high grade serous tumors, earlier onset diagnosis, and have ovarian/breast cancer within the family (Cunningham 2014). The variant was also identified in dbSNP (ID: rs80358815) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; HGMD, Clinvitae database (as pathogenic), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports; in addition to being classified as pathogenic by BIC and Ambry Genetics, likely pathogenic by Counsyl, and classification not provided by Invitae), GeneInsight COGR database (2X, classified as pathogenic and likely pathogenic by 2 clinical laboratories), the BIC database (14X with pathogenic clinical importance), and UMD (1X as a causal variant). The variant was also identified by our laboratory in 1 individual(s) with ovarian cancer.The p.Ser1955X variant leads to a premature stop codon at position 1955, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.