ClinVar Genomic variation as it relates to human health

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

Variant summary: BRCA2 c.5351dupA (p.Asn1784LysfsX3) 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 250394 control chromosomes. c.5351dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Neuhausen_1998, vanderHout_2006, Stegel_2011, Solano_2016). 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. Ten 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.

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 breast and ovarian cancer and is considered a founder pathogenic variant in individuals of Dutch ancestry (Verhoog 1999, Peelen 2000, Spitzer 2000, Janavicius 2010, Walsh 2011, Kang 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 5579insA; This variant is associated with the following publications: (PMID: 23199084, 17591843, 11506493, 23364291, 28127413, 21190077, 28918466, 29084914, 25863477, 10638982, 21232165, 10550133, 22006311, 15010701, 25256924, 10699917, 10451700, 25103822, 27425403, 9585613, 29907814, 16683254, 30103829, 29335924, 30186769, 30702160, 33067490, 31589614, 32733560)

This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5579insA and 5573insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9585613, 10638982, 11597388, 21232165, 22006311, 25863477, 29084914, 29335924) and is reported as a founder mutation in the Netherlands (PMID: 9585613, 11597388). 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.

PVS1, PS4_STR PM2_SUP

This sequence change creates a premature translational stop signal (p.Asn1784Lysfs*3) 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 ovarian cancer (PMID: 10550133, 21232165, 22006311, 25863477). This variant is also known as 5579insA and 5579dupA. ClinVar contains an entry for this variant (Variation ID: 37960). For these reasons, this variant has been classified as Pathogenic.

The BRCA2 c.5351dup; p.Asn1784LysfsTer3 variant (rs80359507), also known as 5579insA, is reported in the literature in numerous individuals with breast and ovarian cancer and has been described as a founder mutation in the Dutch population (Jakimovska 2018, Verhoog 1999, Verhoog 2001, Walsh 2011). This variant is also reported in ClinVar (Variation ID: 37960) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the available information, this variant is considered to be pathogenic. References: Jakimovska M et al. BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia. Breast Cancer Res Treat. 2018 Apr;168(3):745-753. PMID: 29335924. Verhoog LC et al. Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol. 1999 Nov;17(11):3396-402. doi: 10.1200/JCO.1999.17.11.3396. PMID: 10550133. Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001 Nov;37(16):2082-90. PMID: 11597388. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311.

The c.5351dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 5351, causing a translational frameshift with a predicted alternate stop codon (p.N1784Kfs*3). This mutation has been reported in multiple families with breast and/or ovarian cancer (Verhoog LC et al. J. Clin. Oncol. 1999 Nov;17:3396-402; Peelen T et al. Br. J. Cancer. 2000 Jan;82:151-6; Spitzer E et al. Int. J. Cancer. 2000 Feb;85:474-81; van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168:745-753), and has been described as a Dutch founder mutation based on haplotype analysis (Neuhausen SL et al. Am. J. Hum. Genet. 1998 Jun;62:1381-8; Janaviius R. EPMA J. 2010 Sep;1:397-412). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 5579insA and 5573insA 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.