ClinVar Genomic variation as it relates to human health

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

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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in association with breast and/or ovarian cancer (Dez 2003, Kwong 2009, Papi 2009, Vaidyanathan 2009, Juwle 2012, Dodova 2015); Not observed in large population cohorts (Lek et al., 2016); Also known as 6079del4 or 6079_6082delAGTT; This variant is associated with the following publications: (PMID: 25893891, 10660329, 19353265, 18821011, 22752604, 15131399, 26183948, 26681312, 18528753, 22970155, 26187060, 19805903, 12955716, 29335924, 29084914, 29470806, 30128899, 29487695, 11920621, 30702160, 32854451)

The BRCA2 c.5851_5854delAGTT; p.Ser1951fs variant (also known as 6079delAGTT) has been reported in several individuals with hereditary breast and ovarian cancer syndrome (Dodova 2015, Juwle 2012, Kwong 2012, Papi 2009, Vaidyanathan 2009). This variant is reported in ClinVar (Variation ID: 38001), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). This variant creates a frameshift and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for c.5851_5854delAGTT: https://www.ncbi.nlm.nih.gov/clinvar/variation/38001/ Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015 Jul 17;15:523. Juwle A et al. BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity. Med Oncol. 2012 Dec;29(5):3272-81. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012;7(9):e43994. Papi L et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. 2009 Oct;117(3):497-504. Vaidyanathan K et al. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation. J Biosci. 2009 Sep;34(3):415-22.

Variant summary: BRCA2 c.5851_5854delAGTT (p.Ser1951TrpfsX11) 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 was absent in 251070 control chromosomes. c.5851_5854delAGTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Kwong_2012, Juwle_2012, Diez_2003, etc). 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.

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 32854451 (2020), 30702160 (2019), 29487695 (2018), 29470806 (2018), 29335924 (2018), 29084914 (2018), 26183948 (2015)). Based on the available information, this variant is classified as pathogenic.

This variant deletes 4 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 in individuals affected with breast and ovarian cancer (PMID: 12955716, 18821011, 25186627, 26183948, 27153395, 27882536, 29487695, 29335924, 29470806, 30430080, 32438681, 32854451, 33471991, 34101484, 34680387, DOI: https://doi.org/10.1515/tjb-2019-0424, Leiden Open Variation Database DB-ID BRCA2_002145, Color internal data). 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.

We found this variant in a 67-year-old female with unilateral breast cancer with family history of breast cancer.

This sequence change creates a premature translational stop signal (p.Ser1951Trpfs*11) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18821011, 19805903, 22752604, 22970155, 26183948, 27882536, 29335924, 29487695). This variant is also known as 6079delAGTT. ClinVar contains an entry for this variant (Variation ID: 38001). For these reasons, this variant has been classified as Pathogenic.

The c.5851_5854delAGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5851 to 5854, causing a translational frameshift with a predicted alternate stop codon (p.S1951Wfs*11). This alteration has been reported in multiple breast and/or ovarian cancer families across various ethnicities (Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Vaidyanathan K et al. J. Biosci. 2009 Sep;34:415-22; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168(3):745-753; Fanale D et al. Cancers (Basel), 2020 Aug;12:; Wessman S et al. Cancers (Basel), 2021 Oct;13:). Of note, this alteration is also designated as 6079_6082delAGTT and 6079delAGTT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

The BRCA2 p.Ser1951TrpfsX11 variant was identified in 9 of 3458 proband chromosomes (frequency: 0.008) from individuals with breast cancer or hereditary breast and ovarian cancer families (Diez 2003 12955716, Juwle 2012, Kurian 2008, Lubinski 2004, Papi 2009, Vaidyanathan 2009). The variant was not detected in 500 control chromosomes from healthy individuals from these studies. The variant was also identified in dbSNP (ID: rs80359543), LOVD, UMD (6X as a causal variant), and the BIC database (11X with clinical importance). The p.Ser1951TrpfsX11 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1951and leads to a premature stop codon 11 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.

The BRCA2 c.5851_5854delAGTT variant is predicted to result in a frameshift and premature protein termination (p.Ser1951Trpfs*11). This variant has been reported in multiple individuals with breast and/or ovarian cancer across various ethnicities (see for example, Bahsi and Erdem. 2020. Turk J Biochem. 45(1): 83–90; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S2, Liu et al. 2021. PubMed ID: 33461583) and in a patient with lung adenocarcinoma (Table S1, Reckamp et al. 2021. PubMed ID: 33858029). This variant has also been reported in four individuals from a hereditary breast and ovarian cancer (HBOC) family (Supplementary file 1, Majidzadeh-A et al. 2022. PubMed ID: 33754277). This variant is interpreted as pathogenic by the hereditary breast, ovarian and pancreatic cancer variant curation expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38001/). An alternate nucleotide change affecting the same amino acid (c.5850_5853delTAGT:p.Ser1951TrpfsTer11) has been reported in individuals affected with HBOC and classified to be pathogenic (BRCA2 supplementary table, Gao et al. 2020. PubMed ID: 31825140). Frameshift variants in BRCA2 are expected to be pathogenic (Borg et al. 2010. PubMed ID: 20104584). The c.5851_5854delAGTT variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.