Submissions for variant NM_000059.4(BRCA2):c.2957dup (p.Asn986fs)

dbSNP: rs80359365

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077700	SCV000300575	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044094	SCV000072107	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn986Lysfs*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 a personal or family history of breast or ovarian cancer (PMID: 16683254, 24156927, 26219728). ClinVar contains an entry for this variant (Variation ID: 51378). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000160274	SCV000210727	pathogenic	not provided	2023-10-23	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 16683254, 24156927, 26219728); 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 3185dupA; This variant is associated with the following publications: (PMID: 26219728, 24156927, 16683254, 25685387, 32918181, 31892343, 30322717, 32318955, 30787465, 32295079, 33471991, 36623239)
Ambry Genetics	RCV000213454	SCV000274222	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The c.2957dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 2957, causing a translational frameshift with a predicted alternate stop codon. This alteration has been detected in multiple individuals/families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Tea MK et al. Maturitas 2014 Jan;77:68-72; Finch A et al. Clin. Genet. 2016 Mar;89:304-11). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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	RCV000077700	SCV000326792	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160274	SCV000600537	pathogenic	not provided	2021-06-25	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with a personal or family history of breast and ovarian cancer in the published literature (PMID: 29446198 (2018), 26219728 (2016) and 16683254 (2006)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213454	SCV000683515	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-31	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 has been reported in individuals with a personal or family history of breast, ovarian, pancreatic, or prostate cancer (PMID: 16683254, 24156927, 26219728, 29446198, 32918181) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001395). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000044094	SCV001251932	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044094	SCV002074357	pathogenic	Hereditary breast ovarian cancer syndrome	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2957dupA (p.Asn986LysfsX2) 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 248532 control chromosomes (gnomAD). c.2957dupA has been reported in the literature in multiple individuals with personal and/or family history of tumors that belong to the Hereditary Breast and Ovarian Cancer Syndrome spectrum (e.g. van der Hout_2006, Tea_2014, Rebbeck_2018, Power_2021). 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. Nine ClinVar submitters, including one expert panel (ENIGMA), have assessed the variant since 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000160274	SCV004184305	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Baylor Genetics	RCV003473322	SCV004210394	pathogenic	Familial cancer of breast	2023-02-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160274	SCV004238668	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077700	SCV004242473	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-07-10	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP,
All of Us Research Program, National Institutes of Health	RCV000077700	SCV004845086	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	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 has been reported in individuals with a personal or family history of breast, ovarian, pancreatic, or prostate cancer (PMID: 16683254, 24156927, 26219728, 29446198, 32918181) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001395). 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000044094	SCV005374659	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-28	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PVS1 (very strong pathogenic): Null variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism, PM2 (supporting pathogenic): not in gnomAD, PM5 (medium pathogenic): See ENIGMA Specifications Table 4 for PM5_PTC code strengths applicable per exon (PM5_PTC_S)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795966	SCV005418360	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Fulgent Genetics, Fulgent Genetics	RCV004795966	SCV005633894	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-04-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077700	SCV000109503	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077700	SCV000146148	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044094	SCV000587649	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353682	SCV000591839	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Asn986LysfsX2 duplication variant was not identified in the literature but was identified in the BIC database 2x as clinically important. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 986 and leads to a premature stop codon 2 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 for 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 criteria to be classified as pathogenic.
CZECANCA consortium	RCV001270987	SCV001451799	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing