ClinVar Genomic variation as it relates to human health

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

The BRCA2 c.5303_5304delTT; p.Leu1768fs variant (rs80359505), also known as 5531delTT, is reported in the literature in individuals and families affected with breast, ovarian, or prostate cancer (Castro 2013, Gayther 2000, Gutierrez Espeleta 2012, Kraus 2017, Tea 2014). In at least one family, this variant was observed in multiple individuals affected with breast cancer (Gutierrez Espeleta 2012). This variant is found on only one chromosome in the Genome Aggregation Database (1/250376 alleles), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37957). This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Castro E et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. Gayther SA et al. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res. 2000 Aug 15;60(16):4513-8. Gutierrez Espeleta GA et al. BRCA1 and BRCA2 mutations among familial breast cancer patients from Costa Rica. Clin Genet. 2012 Nov;82(5):484-8. Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72.

Variant summary: BRCA2 c.5303_5304delTT (p.Leu1768ArgfsX5) 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 (c.5471dupA, p.Asn1824fsX5; c.5576_5579delTTAA, p.Ile1859fsX3; c.5682C>G, p.Tyr1894X). The variant allele was found at a frequency of 4e-06 in 250376 control chromosomes (gnomAD and one publication). The variant, c.5303_5304delTT, has been reported in the literature in multiple individuals affected with breast and ovarian cancer (Espeleta_2012, Tea_2014, Kraus_2016, Rebbeck_2018). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant c.5303_5304del, p.(Leu1768Argfs*5) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was unknown.The variants does not (fully) explain the NDD in this individual

The BRCA2 c.5303_5304delTT variant is classified as Pathogenic (PVS1, PM2_Supporting) This BRCA2 c.5303_5304delTT variant is predicted to cause a shift in the reading frame at codon 1768. The variant is rare in population databases (PM2). The variant has been reported in dbSNP (rs80359505) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 37957). It has not been reported in HGMD. literature: This variant has been reported in the scientific literature in individuals with ovarian, pancreatic and prostate cancer as well as families with prostate and breast cancer (Shindo et al., 2017, PMID:28767289, Gutiérrez Espeleta et al., 2012, PMID:21895635, Gayther et al., 2000, PMID:10969800, Fisher et al., 2008, PMID:18182994, Lecarpentier et al., 2012, PMID:22762150, Castro et al., 2013, PMID:23569316, Ashton-Prolla et al., 2014, PMID:24764757, Tea et al., 2014, PMID:24156927, Rebeck et al., 2018, PMID:29446198).

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; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Gayther 2000, Gutierrez Espeleta 2012, Song 2014, Shindo 2017, Hoyer 2018); 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 5531_5532del; 5331delTT; This variant is associated with the following publications: (PMID: 21895635, 24728189, 24764757, 34657373, 29922827, 28888541, 29625052, 10969800, 20002770, 24156927, 20043088, 28127413, 23569316, 21952622, 21702907, 22711857, 22762150, 27225637, 23747895, 28767289, 29446198, 30257646, 30720243, 34399810, 32885271, 30787465, 33087929, 33758026, 35264596, 27616075, 36169650, 20104584, 24312913)

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250376 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21895635 (2012), 22762150 (2012), 28888541 (2017), 30257646 (2018), 32885271 (2021), 33471991 (2021), 34657373 (2022), and 33758026 (2022)), prostate cancer (PMID: 10969800 (2000)), and pancreatic cancer (PMID: 28767289 (2017), 29625052 (2018), and 34399810 (2021)). Based on the available information, this variant is classified as pathogenic.

This variant deletes 2 nucleotides in exon 11 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 has been reported 1 individual affected with ovarian cancer, 6 individuals affected with breast cancer (PMID: 21895635, 22711857, 22762150, 35264596, 33471991; Leiden Open Variation Database DB-ID BRCA2_002874), and has been identified in 16 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/250376 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.Leu1768Argfs*5) 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 (rs80359505, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, and prostate cancer (PMID: 10969800, 21895635, 22762150). This variant is also known as 5531delTT. ClinVar contains an entry for this variant (Variation ID: 37957). For these reasons, this variant has been classified as Pathogenic.

The p.Leu1768ArgfsX5 variant in BRCA2 has been reported in at least 15 individuals with BRCA2-related cancers and segregated with disease in at least 1 individual from one family (Gayther 2000, Gutiérrez Espeleta 2012, Shindo 2017, Tea 2014, Alsop 2012, Lecarpentier 2012, Castro 2013, Kraus 2017, Mitra 2008, BIC database). It has also been identified in 1/113142 European 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 1768 and leads to a premature termination codon 5 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: 37957). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.

The c.5303_5304delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5303 to 5304, causing a translational frameshift with a predicted alternate stop codon (p.L1768Rfs*5). This mutation has been reported in multiple HBOC families to date (Gayther SA et al. Cancer Res. 2000 Aug;60:4513-8; Gutiérrez Espeleta GA et al. Clin. Genet. 2012 Nov;82:484-8; Tea MK et al. Maturitas. 2014 Jan;77:68-72). Of note, this alteration is also designated as 5531delTT in some 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.

PVS1,PS4_Very Strong,PM2

The p.Leu1768Argfs*5 variant in the BRCA2 gene, also described as c.5531delTT in the literature, has been previously reported in at least 4 unrelated individuals with hereditary breast and ovarian cancer (Alsop et al., 2012; Gutiérrez Espeleta et al., 2012; Kraus et al., 2016). This variant has been identified in 1/113,142 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Leu1768Argfs*5 variant results in a 2 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 5 amino acids downstream. Heterozygous loss of function is an established mechanism of disease for the BRCA2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu1768Argfs*5 variant as pathogenic for autosomal dominant BRCA2-associated hereditary breast and ovarian cancer based on the information above. [ACMG evidence codes used: PVS1; PS4_Supporting; PM2]

The BRCA2 p.Leu1768Argfs*5 variant was identified in the literature however the frequency of this variant in an affected population was not provided (Copson 2018). The variant was also identified in the following databases: dbSNP (ID: rs80359505) as “With Pathogenic allele”, ClinVar and Clinvitae databases (11x classified as pathogenic by ENIGMA, University of Cambridge, Ambry Genetics, Invitae, GeneDx, Color Genomics, Laboratory Corporation of America, BIC, Medical University Innsbruck, Sharing Clinical Reports, and Women's College Hospital), LOVD 3.0 (9 entries classified as affects function), UMD-LSDB (2 entries classified as causal), BIC Database (5 entries classified as pathogenic), and ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in the COGR, COSMIC, MutDB, or Zhejiang Colon Cancer databases. The variant was identified in control databases in 1 of 245386 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 1 of 111220 chromosomes (freq: 0.000009); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The c.5303_5304del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1768 and leads to a premature stop codon 5 codons downstream. 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.