Submissions for variant NM_000059.4(BRCA2):c.4131_4132insTGAGGA (p.Thr1378Ter)

dbSNP: rs80359429

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)	RCV000113276	SCV000324219	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000215361	SCV000276996	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing	The c.4131_4132insTGAGGA pathogenic mutation (also known as p.T1378*), located in coding exon 10 of the BRCA2 gene, results from an in-frame TGAGGA insertion between nucleotide positions 4131 and 4132. This changes the amino acid from a threonine to a stop codon within coding exon 10. This mutation (designated as 4359ins6) has been previously reported in a pair of identical female twins with breast cancer (Delgado L et al. Cancer Genet. and Cytogenet. 2002 Feb;133:24-8). This alteration was identified in multiple large, worldwide studies of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Laitman Y et al. Hum Mutat. 2019 Nov;40(11):e1-e23; Santonocito C et al. Cancers (Basel). 2020 May 19;12(5):1286.). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485082	SCV000296512	pathogenic	not provided	2021-09-29	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with personal and/or family history of breast and/or ovarian in the published literature (PMIDs: 11890985 (2002), 23096105 (2012), 25896959 (2015), 27376475 (2016), 31065452 (2019), 32438681 (2020), and 33471991 (2021)). The variant has also been identified in one individual with pancreatic ductal adenocarcinoma (PMID: 25940717 (2015)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113276	SCV000326976	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465953	SCV000549711	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1378*) 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 pancreatic ductal adenocarcinoma and a personal and/or family history of breast cancer (PMID: 11890985, 20927582, 23096105, 25896959, 25940717, 27376475). This variant is also known as Ins 4359 (TGAGGA), 4359ins6, or 1377insXG (InsTGAGGA). ClinVar contains an entry for this variant (Variation ID: 126037). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000485082	SCV000564776	pathogenic	not provided	2021-06-04	criteria provided, single submitter	clinical testing	Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4359_4360insTGAGGA or 4359ins6; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27535533, 31447099, 31065452, 30128899, 31209999, 29907814, 25896959, 27376475, 25940717, 11890985, 20927582)
Color Diagnostics, LLC DBA Color Health	RCV000215361	SCV000688851	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This variant inserts 6 nucleotides in exon 11 of the BRCA2 gene, creating a 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, ovarian, and pancreatic cancer (PMID: 11890985, 18703817, 20927582, 23096105, 25940717, 32438681). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000465953	SCV000694745	pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4131_4132insTGAGGA (p.Thr1378X) 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. The variant was absent in 246356 control chromosomes (gnomAD). c.4131_4132insTGAGGA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Delgado_2002, Palma_2008, Ding_2011, Nicolussi_2019, Vietri_2012). 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. Eight other ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000113276	SCV000839934	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-25	criteria provided, single submitter	clinical testing	This c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene has been reported in multiple breast cancer and pancreatic cancer patients [PMID: 11890985, 25940717] while not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.4131_4132insTGAGGA (p.Asn1377_Thr1378insTer) variant in the BRCA2 gene is classified as pathogenic.
Mendelics	RCV002247496	SCV002518603	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477264	SCV002796232	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002247496	SCV004210518	pathogenic	Familial cancer of breast	2022-08-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492436	SCV004240310	pathogenic	Breast and/or ovarian cancer	2022-09-23	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113276	SCV000146378	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing