Submissions for variant NM_000059.4(BRCA2):c.1842dup (p.Asn615Ter)

dbSNP: rs80359312

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112985	SCV000282364	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112985	SCV000326624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480390	SCV000568456	pathogenic	not provided	2016-05-10	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted BRCA2 c.1842dupT at the cDNA level and p.Asn615Ter (N615X) at the protein level. The normal sequence, with the base that is duplicated in braces, is TAAT[T]AACT. The duplication creates a nonsense variant, which changes an Asparagine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 1842dupT, also denoted BRCA2 2070dupT and 2070insT using alternate nomenclature, has been observed in at least one breast/ovarian cancer family (Esteban Cardeñosa 2010). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000562038	SCV000666082	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing	The c.1842dupT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of T at nucleotide position 1842, causing a translational frameshift with a predicted alternate stop codon (p.N615*). This alteration has been reported in multiple individuals with personal and/or family history of hereditary breast and/or ovarian cancer (Esteban Cardeñosa E et al. Breast Cancer Res. Treat. 2010 May;121:257-60; Ruiz A et al. Biomed Res Int 2014 Jun;2014:542541). Of note, this alteration is also designated as 2070dupT 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589322	SCV000694577	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1842dupT (p.Asn615X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 117182 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals (e.g., Jimenez_Familial Cancer_2013; Hondow_BMC Cancer_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480390	SCV000887764	pathogenic	not provided	2016-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589322	SCV001584897	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn615*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51212). This variant is also known as 2070dupT. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20033483). This variant is not present in population databases (gnomAD no frequency).
Baylor Genetics	RCV003473308	SCV004212856	pathogenic	Familial cancer of breast	2022-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000562038	SCV004361239	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 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 with a personal or family history of breast and/or ovarian cancer (PMID: 20033483, 23479189, 29446198, 30240327, 31090900, 33403015, 33573335). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000589322	SCV004847744	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-28	criteria provided, single submitter	clinical testing	The p.Asn615X (c.1842dupT) variant in BRCA2 has been reported in at least 3 individuals with BRCA2-related cancers (Esteban Cardeñosa 2010, BIC database). Additionally, it was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 51212). This variant was absent from large population studies. The p.Asn615X (c.1842dupT) variant is an insertion of a single nucleotide, creating a premature termination codon at position 57, which is 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112985	SCV000145964	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing