Submissions for variant NM_000059.4(BRCA2):c.4276dup (p.Thr1426fs)

dbSNP: rs80359438

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031472	SCV000300731	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	RCV000130745	SCV000185636	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	The c.4276dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4276, causing a translational frameshift with a predicted alternate stop codon (p.T1426Nfs*12). This mutation has been identified in families with hereditary breast and/or ovarian cancer (Lubinske J et al. Fam Cancer. 2004;3(1):1-10; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). Of note, this mutation is also designated as 4504insA 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031472	SCV000327005	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130745	SCV000683609	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-23	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 that is expected to trigger nonsense-mediated decay. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five families suspected of being affected with hereditary breast and ovarian cancer (PMID: 15131399, 29446198). 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.
GeneDx	RCV000657226	SCV000778952	pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing	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; Reported in association with hereditary breast and/or ovarian cancer (Lubinski et al., 2004); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4504dupA and 4504insA; This variant is associated with the following publications: (PMID: 28281021, 28152038, 29446198, 31853058, 33084842, 32918181, 15131399, 33087929)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496461	SCV000918958	pathogenic	Hereditary breast ovarian cancer syndrome	2021-10-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4276dupA (p.Thr1426AsnfsX12) 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 244880 control chromosomes (gnomAD). c.4276dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Lubinski_2004 and Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and two expert panels (CIMBA and ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496461	SCV001585114	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1426Asnfs*12) 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 a personal and/or family history of BRCA2-related disease (PMID: 15131399). This variant is also known as 4504insA (Stop 1437). ClinVar contains an entry for this variant (Variation ID: 37891). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496461	SCV004848261	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Thr1426AsnfsX12 variant in BRCA2 (resulting from c.4276dupA) has been reported in at least 5 individuals with BRCA2-related cancers (Lubinski 2004, Crawford 2017, BIC database). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1426 and leads to a premature termination codon 12 amino acids downstream. This alteration is then 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). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37891). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Baylor Genetics	RCV004566770	SCV005059036	pathogenic	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031472	SCV000054077	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031472	SCV000146399	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-08-16	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496461	SCV000587707	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research