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.Phe1870*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer and Fanconi anemia (PMID: 12065746, 21232165, 22729890, 22923021, 24156927). This variant is also known as 5837 TC to AG. ClinVar contains an entry for this variant (Variation ID: 51890). For these reasons, this variant has been classified as Pathogenic.

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. This variant has been reported in individuals affected with breast cancer (PMID: 18284688, 21232165, 22729890, 28324225, 34680878) and Fanconi anemia (PMID: 12065746). In a large breast cancer case-control study conducted by the Breast Cancer Association Consortium, this variant was reported in 2/60466 cases and 0/53461 controls (p-value=0.502) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001645). 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.

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; Also known as 5837_5838delTCinsAG; This variant is associated with the following publications: (PMID: 27003155, 21232165, 22923021, 28056804, 28324225, 16683254, 25447315, 16825431, 24156927, 22729890, 25583207, 23583677, 15689453, 28152038, 28288110, 24301060, 16115142, 15645491, 21719596, 30322717, 32341426, 33471991, 29446198, 36721989, 38219492, 18284688, 34680878, 12065746)

The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870* and 5837TC>AG), located in coding exon 10 of the BRCA2 gene, results from the deletion and insertion of 2 nucleotides at positions 5609 and 5610. This changes the amino acid at codon 1870 from a phenylalanine to a stop codon. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel et al. BMC Med Genet. 2011 Jan 14;12:9; Becker et al. Breast Cancer Res Treat. 2012 Aug;135(1):167-75; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72) and in an individual with Fanconi Anemia (Howlett et al. Science. 2002 Jul 26;297(5581):606-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.

The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870*), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TC and insertion of AG at nucleotide positions 5609 to 5610. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Tea MK et al. Maturitas 2014 Jan;77:68-72; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238), and in an individual with Fanconi Anemia (Howlett NG et al. Science 2002 Jul;297:606-9). Of note, this alteration is also designated as 5837TC>AG 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.

Variant summary: BRCA2 c.5609_5610delinsAG (p.Phe1870X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247384 control chromosomes. c.5609_5610delinsAG has been reported in the literature in individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (Becker_2012, Novakovic_2012, Stegel_2011, Tea_2014) and observed in a compound heterozygous Fanconi Anemia patient (Howlett_2002). 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. 12 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.