Submissions for variant NM_000059.4(BRCA2):c.3545_3546del (p.Gln1181_Phe1182insTer)

dbSNP: rs80359388

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031427	SCV000282379	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	RCV000044219	SCV000072232	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1182*) 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 present in population databases (rs748852670, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15131399, 20104584, 24156927, 25884701). This variant is also known as 3772delTT, c.3773delTT, and p.Phe1182Terfs. ClinVar contains an entry for this variant (Variation ID: 37846). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074527	SCV000108612	pathogenic	not provided	2020-11-04	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; Observed as heterozygous in individuals with a personal and/or family history of BRCA2-related cancers, and as compound heterozygous in an individual with Fanconi anemia (Lubinski 2004, Cavallone 2010, Tea 2014, Belanger 2015, Malric 2015, Shindo 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3772delTT or 3773delTT; This variant is associated with the following publications: (PMID: 20104584, 21952622, 15131399, 25884701, 24156927, 21324516, 26986251, 25381700, 15382066, 20694749, 16905680, 28166811, 28767289, 21568838, 18042939, 17416853, 16825431, 16141007, 15796958, 15197194, 12677558, 9497246, 22430266, 26014432, 26295337, 29339979, 29084914, 30128899, 30609409, 30720243, 31851867, 31409081, 32255556)
Counsyl	RCV000031427	SCV000154067	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-31	criteria provided, single submitter	literature only
Ambry Genetics	RCV000131093	SCV000186023	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-13	criteria provided, single submitter	clinical testing	The c.3545_3546delTT (p.F1182*) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 2 nucleotides from position 3545 to 3546. This changes the amino acid from a phenylalanine to a stop codon at amino acid 1182. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.002% (5/250970) total alleles studied. The highest observed frequency was 0.004% (5/113332) of European (non-Finnish) alleles. This variant has been well described in the literature and has been seen in multiple individuals with a personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome, including several French-Canadian families (Lubinski, 2004; Oros, 2004; Simard, 2007; Borg, 2010; Borg, 2010; Belanger, 2015; Labidi-Galy, 2018). Of note, this alteration is also designated as 3773delTT and 3772delTT in published literature. Based on the available evidence, this alteration is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074527	SCV000296692	pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000044 (5/113332 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is also known as 3773delTT, and it has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25884701 (2015), 21324516 (2011), 20694749 (2010), 20104584 (2010)). 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	RCV000031427	SCV000326880	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031427	SCV000605663	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044219	SCV000605795	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.Phe1182X variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database (https://research.nhgri.nih.gov/bic/), Lubinski 2004 PMID: 15131399, Borg 2010 PMID: 20104584, Cavallone 2010 PMID: 20694749, Zhang 2011 PMID: 21324516, Finkelman 2012 PMID: 22430266, Tea 2014 PMID: 24156927, Belanger 2015 PMID: 25884701, Polsler 2016 PMID: 26014432, Shindo 2017 PMID: 28767289, Heramb 2018 PMID: 29339979, Labidi-Galy 2018 PMID: 29084914, Cremin 2020 PMID: 32255556). It has also been identified in 0.004% (5/113332) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1182, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Furthermore, the p.Phe1182X variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282379.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV000131093	SCV000683566	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-13	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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 at least five individuals and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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.
GeneKor MSA	RCV000074527	SCV000693564	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes 2 nucleotide from exon 11 of the BRCA2 mRNA (c.3545_3546delTT), creating a premature translational stop signal at codon 1182 (p.Phe1182*). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 15131399 24156927, 25884701, 20104584) and is also known as 3772delTT and c.3773delTT. The mutation database ClinVar contains entries for this variant (Variation ID: 37846).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044219	SCV000694703	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3545_3546delTT (p.Phe1182X) 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 allele was found at a frequency of 2e-05 in 250970 control chromosomes. c.3545_3546delTT 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735540	SCV000902197	pathogenic	Breast and/or ovarian cancer	2023-04-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074527	SCV001446508	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000074527	SCV002049213	pathogenic	not provided	2021-02-25	criteria provided, single submitter	clinical testing	The BRCA2 c.3545_3546delTT; p.Phe1182Ter variant (rs80359388), also known as 3772delTT and 3773delTT, has been reported in multiple individuals and families with breast, ovarian, and/or pancreatic cancer (Belanger 2015, Borg 2010, Cremin 2020, Labidi-Galy 2018, Lubinski 2004, Shindo 2017, Tea 2014). This variant is found on only five chromosomes (5/250970 alleles) in the Genome Aggregation Database. This variant deletes two nucleotides, induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Belanger MH et al. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. J Ovarian Res. 2015 Mar 27;8:1. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Cremin C et al. Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening. Cancer Med. 2020 Jun;9(11):4004-4013. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72.
Johns Hopkins Genomics, Johns Hopkins University	RCV000031427	SCV002570259	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-04	criteria provided, single submitter	clinical testing	This BRCA2 variant (rs80359388) is rare (<0.1%) in a large population dataset (5/250970 total alleles; 0.002%; no homozygotes) and has an entry in ClinVar11. This nonsense variant, also known as 3772delTT and 3773delTT, has been reported in multiple unrelated individuals affected with hereditary breast and ovarian cancer. This frameshift variant creates a premature termination codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider c.3545_3546del to be pathogenic.
Revvity Omics, Revvity	RCV000074527	SCV003812464	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473168	SCV004210367	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000074527	SCV004700723	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
All of Us Research Program, National Institutes of Health	RCV004803020	SCV004845179	pathogenic	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides 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 at least five individuals and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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.
Fulgent Genetics, Fulgent Genetics	RCV005003412	SCV005633902	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	2024-03-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031427	SCV000054032	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031427	SCV000146255	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031427	SCV000212017	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353741	SCV000591867	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Phe1182X variant has been identified in 4 out of 5086 proband chromosomes (frequency 0.001) in individuals with unilateral, contralateral and familial breast and ovarian cancer phenotype; however no control chromosomes were included in these studies (Lubinski 2004, Borg 2010). It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359388) however no frequency information was provided. The variant was identified in ClinVar from 6 sources in at least 23 individuals from different ethnic backgroungs (GeneDx, BIC, Ambry, and SCRP derived from Myriad reports all classify this variant as pathogenic; Counsyl classified this variant as Likely pathogenic). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence and leads to a premature stop codon at position 1182. This alteration is predicted to cause a truncated or absent BRCA2 protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735540	SCV000863678	pathogenic	Breast and/or ovarian cancer	2016-04-07	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001391215	SCV001593131	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000074527	SCV001739576	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074527	SCV001905756	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000074527	SCV001928861	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031427	SCV002588863	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532438	SCV004118162	pathogenic	BRCA2-related disorder	2024-03-26	no assertion criteria provided	clinical testing	The BRCA2 c.3545_3546delTT variant is predicted to result in premature protein termination (p.Phe1182*). This variant, also known as 3772delTT and 3773delTT, has been reported in individuals with breast, ovarian, and pancreatic cancer (see for example - Lubinski et al. 2004. PubMed ID: 15131399; Shindo et al. 2017. PubMed ID: 28767289; Labidi-Galy et al. 2018. PubMed ID: 29084914, Table S2; Heramb et al. 2018. PubMed ID: 29339979). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37846). This variant is interpreted as pathogenic.