Submissions for variant NM_000059.4(BRCA2):c.1257del (p.Cys419fs)

dbSNP: rs80359272

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031314	SCV000300412	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	RCV000043768	SCV000071781	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys419Trpfs*11) 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 breast and/or ovarian cancer (PMID: 15131399, 22762150, 25682074). This variant is also known as 1485delT. ClinVar contains an entry for this variant (Variation ID: 37733). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130282	SCV000185127	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The c.1257delT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at position 1257, causing a translational frameshift with a predicted alternate stop codon (p.C419Wfs*11). This mutation (also designated as 1485delT) has been identified in multiple high-risk breast/ovarian cancer families (Lubinski J et al. Fam. Cancer 2004;3(1):1-10; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Santonocito C et al. Cancers (Basel), 2020 May;12). 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	RCV000031314	SCV000326527	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480855	SCV000568453	pathogenic	not provided	2020-07-07	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database.; Observed in individuals with BRCA2-related cancers (Wong-Brown 2015, Petridis 2019, Santonocito 2020); Not observed in large population cohorts (Lek 2016); Also known as BRCA2 c.1485delT; This variant is associated with the following publications: (PMID: 25682074, 15131399, 26315209, 22762150, 31263054, 32438681, 31447099)
Color Diagnostics, LLC DBA Color Health	RCV000130282	SCV000683409	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-01	criteria provided, single submitter	clinical testing	This variant deletes 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15131399, 22762150, 25682074, 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	RCV000043768	SCV000694526	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1257delT (p.Cys419TrpfsX11) 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 248052 control chromosomes. c.1257delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000031314	SCV000785374	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480855	SCV001133673	pathogenic	not provided	2019-02-27	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in one symptomatic patient, and not found in general population data.
Baylor Genetics	RCV003460498	SCV004216107	pathogenic	Familial cancer of breast	2023-05-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043768	SCV004847741	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-28	criteria provided, single submitter	clinical testing	The p.Cys419TrpfsX11 variant in BRCA2 has been reported in at least 8 individuals with a personal or family history of breast or ovarian cancer (Lecarpentier 2012, Wong-Brown 2015, Lubinski 2004, BIC database). Additionally, it was classified as Pathogenic on Sep. 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37733). This variant was absent from large population studies. The p.Cys419TrpfsX11 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 419 and leads to a premature termination codon 11 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Sharing Clinical Reports Project (SCRP)	RCV000031314	SCV000053919	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031314	SCV000145841	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	RCV000043768	SCV000587587	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355949	SCV001550980	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Cys419Trpfs*11 variant was identified in 2 of 2428 proband chromosomes (frequency: 0.0008) from individuals or families with hereditary breast and ovarian cancer (Lubinski 2004, Wong 2015). The variant was also identified in dbSNP (ID: rs80359272) as “With Pathogenic allele”, ClinVar (11 x as pathogenic, reviewed by expert panel), Clinvitae (4x), LOVD 3.0 (4x as pathogenic), UMD-LSDB (as causal), BIC Database (3x as pathogenic), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in COGR, Cosmic, MutDB, or Zhejiang University Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1257delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 419 and leads to a premature stop codon at position 429. 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 in 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 laboratory’s criteria to be classified as pathogenic.