Submissions for variant NM_000059.4(BRCA2):c.3860dup (p.Asn1287fs)

dbSNP: rs80359406

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113229	SCV000300675	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.
GeneDx	RCV000497279	SCV000210741	pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted BRCA2 c.3860dupA at the cDNA level and p.Asn1287LysfsX2 (N1287KfsX2) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAA[dupA]TAAT. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 1287, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 3860dupA, previously reported as 4081insA or 4088insA, has been observed previously in association with breast and/or ovarian cancer and is reported to be a founder variant in the Finnish population (Sarantaus 2000, Hartikainen 2007, Karami 2013). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113229	SCV000326928	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000113229	SCV000677677	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000497279	SCV000887800	pathogenic	not provided	2018-07-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772033	SCV000905011	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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 is also known as 4088insA and 4081insA in the literature. This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 11039575, 15642173, 18214034, 29446198). It has been shown that this variant segregates with disease in five individuals of one family (PMID: 18214034). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496333	SCV001577950	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1287Lysfs*2) 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 or at high risk of breast and/or ovarian cancer and hereditary breast and ovarian cancer (HBOC) (PMID: 11039575, 18214034, 29446198). It has also been observed to segregate with disease in related individuals. This variant is also known as 4081insA or 4088insA. ClinVar contains an entry for this variant (Variation ID: 51546). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000772033	SCV002622908	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	The c.3860dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 3860, causing a translational frameshift with a predicted alternate stop codon (p.N1287Kfs*2). This alteration segregated in a Finnish family with histories of breast, ovarian, and prostate cancer (Hartikainen JM et al. Anticancer Res., 2007 27(6C):4295-300). Of note, this alteration is also designated as 4088insA in the 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.
Revvity Omics, Revvity	RCV000497279	SCV003814438	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460578	SCV004216125	pathogenic	Familial cancer of breast	2023-05-19	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113229	SCV000146315	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496333	SCV000587684	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000113229	SCV004243612	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing