ClinVar Genomic variation as it relates to human health

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

Variant summary: BRCA2 c.3860delA (p.Asn1287IlefsX6) 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 allele was found at a frequency of 1.5e-05 in 195552 control chromosomes. c.3860delA has been well reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (example, Rebbeck_2018, Heramb_2018. Sun_2017, Susswein_2016, and Llott_2002). 11 clinical diagnostic laboratories and one expert panel (ENIGMA) 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.

This sequence change creates a premature translational stop signal (p.Asn1287Ilefs*6) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11857748, 12942367, 12955716, 23199084, 24156927, 27393621). ClinVar contains an entry for this variant (Variation ID: 51545). For these reasons, this variant has been classified as Pathogenic.

The p.Asn1287IlefsX6 variant in BRCA2 has been reported in at least 6 individuals with BRCA2-related cancers (Llort 2002, Sun 2017, BIC database). It has also been identified in 1/6886 Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1287 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51545). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.

The c.3860delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 3860, causing a translational frameshift with a predicted alternate stop codon (p.N1287Ifs*6). This alteration has been reported in multiple breast and/or ovarian cancer families to date (Kanaan Y et al. Hum. Genet. 2003 Oct;113(5):452-60; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Zhang J et al. Breast Cancer Res Treat. 2016 Aug;158(3):455-62; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 4088delA 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.

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.

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4088delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 16 individuals affected with breast cancer, including 2 male individuals and 1 individual affected with both breast and ovarian cancer (PMID: 12673801, 12942367, 12955716, 27393621, 32438681, 33471991, 34645131, doi: 10.51505/ijmshr.2021.5213). This variant has been identified in many families affected with breast and/or ovarian cancer and has been reported in 29 families among CIMBA participants (PMID: 18821011, 24156927, 29446198). 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.

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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4088del; This variant is associated with the following publications: (PMID: 18821011, 27167707, 34413315, 32438681, 29884136, 11857748, 23199084, 24156927, 12673801, 26843898, 26681312, 26848529, 27393621, 28480178, 29339979, 28724667, 30702160, 31528241, 31825140, 30787465, 31742824, 33087929, 32885271, 35803546, 34645131, 35864222, 36495689, 33471991)

PM5_strong, PVS1

BRCA2, EXON11, c.3860del, p.Asn1287Ilefs*6, Heterozygous, PathogenicrnThe BRCA2 p.Asn1287Ilefs*6 variant was identified in 8 of 830 proband chromosomes (frequency: 0.01) from African-American, Polish, Italian and Austrian individuals or families with breast or ovarian cancer and was not identified in 326 control chromosomes from healthy individuals (Kanaan 2003, Perkowska 2003, Papi 2009, Singer 2014). The variant was also identified in dbSNP (ID: rs80359406) as “With Pathogenic allele”, ClinVar (classified as pathogenic by an ENIGMA expert panel (2016), Ambry Genetics, Invitae, GeneDx, CIMBA and 10 other submitters), LOVD 3.0, and UMD-LSDB (classified as 5-causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.3860del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1287 and leads to a premature stop codon at position 1292. This alteration is then predicted to result in 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. Assessment Date: 2019/07/15. References (PMIDs): 12942367, 18821011, 12673801, 23772696.