Submissions for variant NM_000059.4(BRCA2):c.5116_5119del (p.Asn1706fs)

dbSNP: rs276174853

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077344	SCV000300829	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000131076	SCV000186006	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The c.5116_5119delAATA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5116 to 5119, causing a translational frameshift with a predicted alternate stop codon (p.N1706Lfs*5). This mutation has been reported in three Korean breast and/or ovarian cancer patients (Jang JH et al. J Hum Genet. 2012 Mar;57(3):212-5; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26). This mutation has also been detected in several early onset breast/ovarian cancer families in Spain, including in a patient with male breast cancer, and has been reported to be a Castilla-Leon founder mutation (Infante M et al. J Hum Genet. 2006;51(7):611-7; Infante M et al. Breast Cancer Res Treat. 2010 Jul;122(2):567-71; Blay P et al. BMC Cancer. 2013 May 17;13:243; Beristain E et al. J Community Genet 2010 Jun; 1(2):91-9; de Juan I et al. Fam. Cancer 2015 Dec; 14(4):505-13). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also reported as 5344_5347delAATA and 5344del4 in the 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.
GeneDx	RCV000044561	SCV000210811	pathogenic	Familial cancer of breast	2013-11-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5116_5119delAATA at the cDNA level and p.Asn1706LeufsX5 (N1706LfsX5) at the protein level according to current HGVS nomenclature guidelines and is also known as c.5344_5347delAATA using alternative nomenclature. The surrounding sequence is GAATA{delAATA}CTGC. The deletion causes a frameshift, changing an Asparagine to a Leucine at codon 1706, and creating a premature stop codon at position 5 of the new reading frame. BRCA2 c.5116_5119delAATA is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This deletion has been reported as a pathogenic variant in an individual with early onset breast cancer and another with familial breast and ovarian cancer (Infante 2006), and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 variants have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 variants also have an increased risk for contralateral breast cancer. Women with BRCA variants whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA variants whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA variants whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 variant include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two variants (one from each parent) in the BRCA2 gene. This condition is characterized by an increased risk for malignancy in children including leukemia and certain solid tumors as well as physical abnormalities and bone marrow failure. If a BRCA2 variant carrier’s partner is also heterozygous for a BRCA2 variant, the risk to have a child with FA is 25% with each pregnancy. The variant is found in BRCA2 panel(s).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077344	SCV000327134	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758904	SCV000887838	pathogenic	not provided	2019-11-11	criteria provided, single submitter	clinical testing
Invitae	RCV000496624	SCV001203966	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1706Leufs*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 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: 16758124, 19949853, 21990299, 22217648, 22798144, 23479189, 23683081, 24448499, 26026974). It is commonly reported in individuals of Spanish ancestry (PMID: 19949853). This variant is also known as 5344delAATA, c.5344_5347delAATA, and c.5112_5115delAATA. ClinVar contains an entry for this variant (Variation ID: 51773). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131076	SCV001348954	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16758124, 21990299, 22460208, 22486713, 22798144, 23479189, 23683081, 25863477, 26026974, 27153395, 32894085). This variant has been identified in 1/231774 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496624	SCV001774541	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5116_5119delAATA (p.Asn1706LeufsX5) 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 4.3e-06 in 231774 control chromosomes. c.5116_5119delAATA has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, 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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consotrium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077344	SCV003932735	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	The pathogenic family mutation in the BRCA2 gene (c.5116_5119delAATA) was detected in this specimen. This sequence change creates a premature translational stop signal (p.Asn1706Leufs*5) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752413577, ExAC 0.002%). This variant has been reported in numerous individuals and families affected with breast and/or ovarian cancer (PMID: 16758124, 26026974, 22217648, 22798144, 24448499, 21990299, 23479189, 23683081). It has been described as a founder mutation in the Spanish population, and has been shown to segregate with breast cancer in several families (PMID: 19949853). This variant is also known as 5344delAATA, c.5344_5347delAATA, and c.5112_5115delAATA in the literature. ClinVar contains an entry for this variant (Variation ID: 51773) with 14 submissions and reviewed by expert panel. Lossoffunction variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic
Baylor Genetics	RCV000044561	SCV004211950	pathogenic	Familial cancer of breast	2023-09-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077344	SCV000109141	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-03-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077344	SCV000146541	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-02-14	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496624	SCV000587745	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353635	SCV000591942	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1706LeufsX5 deletion variant was identified in 10 of 2974 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer (Blay 2013, Infante 2006, Infante 2010, Jang 2012). The variant was also identified in dbSNP (ID: rs276174853) “With pathogenic allele”, HGMD, UMD (1X as a causal variant), and the BIC database (1X with clinical importance). The p.Asn1706LeufsX5 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1706 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.