Submissions for variant NM_000059.4(BRCA2):c.1813del (p.Ile605fs)

dbSNP: rs80359306

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031344	SCV000282362	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203637	SCV000071909	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile605Tyrfs*9) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and prostate cancer (PMID: 11389159, 18824701, 19016756, 20104584, 23035815, 23704984, 24549055). This variant is also known as 2041delA. ClinVar contains an entry for this variant (Variation ID: 37763). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000132177	SCV000187256	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	clinical testing	The c.1813delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1813, causing a translational frameshift with a predicted alternate stop codon (p.I605Yfs*9). This mutation has been identified in multiple individuals with familial and/or early onset breast cancer (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Patmasiriwat P et al. Hum. Mutat. 2002 Sep;20:230; Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110:99-109; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267). Additionally, this mutation was observed in multiple men diagnosed with prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; de Juan I et al. Fam. Cancer. 2015 Dec;14(4):505-13; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). Of note, this alteration is also designated as 2041delA in published literature. 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.
GeneDx	RCV000043896	SCV000210717	pathogenic	not provided	2023-10-10	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 (Bergthorsson et al., 2001; Spearman et al., 2008; Sugano et al., 2008; Hirasawa et al., 2017; Lang et al., 2017; Dudley et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2041delA; This variant is associated with the following publications: (PMID: 12203997, 35448200, 32438681, 23035815, 11389159, 18824701, 19016756, 27062684, 29348823, 29360161, 26026974, 21318380, 20104584, 17851763, 15131399, 12442265, 11802209, 30287823, 30702160, 28294317, 26187060, 26848529, 31454914, 29176636, 33573335, 32365798, 32856869, 33572923, 33646313, 32853339, 31825140, 32338768, 30787465, 36243179, 35264596, 32980694, 32868316, 28888541, 33804961, 33758026, 36988593)
Color Diagnostics, LLC DBA Color Health	RCV000132177	SCV000292131	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-08	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. This variant has been reported in at least 30 individuals affected with breast and/or ovarian cancer (PMID: 11389159, 12203997, 16912212, 17851763, 18824701, 20104584, 23704984, 26026974, 27153395, 28294317, 29348823, 30287823, 32438681) that includes in a breast cancer case-control study where this variant was detected in 18/7051 female cases and 1/11241 unaffected controls (OR=28.7, 95% CI 4.5 to 1190.4) (PMID: 30287823). This variant also has been detected in at least five individuals affected with prostate cancer (PMID: 23035815, 31214711). This variant has been identified in 8/232106 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000043896	SCV000296624	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (3/26880 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 29348823 (2017), 27062684 (2016), 24549055 (2014), 23035815 (2012), 20104584 (2010), 19016756 (2008), 17851763 (2008), 11389159 (2001)). 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	RCV000031344	SCV000326618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000203637	SCV000588079	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203637	SCV000694570	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1813delA (p.Ile605Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.1813dupA (p.Ile605fs), c.1832C>A (p.Ser611X), and c.1842dupT (p.Asn615X)). The variant of interest was not found in the large, broad control population, ExAC (115908 chrs tested). Multiple publications have cited the variant in affected individuals, along with multiple reputable databases/clinical diagnostic laboratories have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Mendelics	RCV000203637	SCV000838763	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031344	SCV001429297	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-27	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000043896	SCV001450072	pathogenic	not provided	2020-01-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000043896	SCV002019164	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132177	SCV002533266	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043896	SCV002550291	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272030	SCV002556798	pathogenic	Familial cancer of breast	2020-08-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002272030	SCV002579644	pathogenic	Familial cancer of breast	2021-11-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000031344	SCV002762801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031344	SCV003932770	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	The BRCA2 c.1813delA (p.Ile605Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in the large, broad control population, ExAC. Multiple publications have cited the variant in affected individuals, along with multiple reputable databases/clinical diagnostic laboratories have cited the variant as "pathogenic." ClinVar has 14 entries for this variant, all of which described it as pathogenic. Therefore, the variant of interest has been classified as Pathogenic.
Baylor Genetics	RCV002272030	SCV004210429	pathogenic	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000043896	SCV004701645	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000203637	SCV004848043	pathogenic	Hereditary breast ovarian cancer syndrome	2018-05-08	criteria provided, single submitter	clinical testing	The p.Ile605fs variant in BRCA2 has been reported in >25 individuals with BRCA2-associated cancers (Bergthorsson 2001, Spearman 2008, Sugano 2008, Borg 2010, Blay 2013, Castera 2014, Azzollini 2016, Hirasawa 2017, Breast Cancer Information Core (BIC) database), and segregated with disease in at least 3 individuals. It was also absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 605 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein. ACMG/AMP Criteria Applied: PVS1, PS4, PM2.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031344	SCV005046011	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000043896	SCV005199773	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031344	SCV005402412	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-06-26	criteria provided, single submitter	clinical testing	The BRCA2 c.1813del (p.Ile605TyrfsTer9) change deletes one nucleotide, causing a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with BRCA2-associated cancers (PMID: 11389159; 19016756; 20104584; 23035815; 23704984; 24549055; 30287823). In summary, this variant meets criteria to be classified as pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000203637	SCV005415548	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-20	criteria provided, single submitter	clinical testing	This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. There are 3810 downstream pathogenic loss of function variants, with the furthest variant being 2815 residues downstream of this variant. This indicates that the region is critical to protein function. The p.Ile605Tyrfs*9 variant is a loss of function variant in the gene BRCA2, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000050.3:p.M1Lfs*44 and 4499 others. For these reasons, this variant has been classified as Pathogenic
Sharing Clinical Reports Project (SCRP)	RCV000031344	SCV000053949	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031344	SCV000145952	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	RCV000203637	SCV000587613	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000043896	SCV001553079	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Ile605Tyrfs*9 variant was identified in 53 of 76928 proband chromosomes (frequency: 0.0007) from individuals or families with breast or ovarian cancer and was present in 2 of 22482 control chromosomes (frequency: 0.00009) from healthy individuals (Bergthorsson 2001, Li 2008, Sugano 2008, Castera 2014, de Juan 2015, Momozawa 2018, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359307) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and eleven other submitters), LOVD 3.0 (18X as pathogenic), and UMD-LSDB (5x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1813del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 605 and leads to a premature stop codon at position 613. 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 breast or 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535574	SCV001749563	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-02-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory for Genotyping Development, RIKEN	RCV003162267	SCV002758328	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031344	SCV005061312	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control