Submissions for variant NM_000059.4(BRCA2):c.5616_5620del (p.Lys1872fs)

dbSNP: rs80359525

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077356	SCV000300906	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	RCV000195403	SCV000072710	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1872Asnfs*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 present in population databases (rs763069721, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15533909, 20104584, 24742220, 25428789, 26681312, 28008555). This variant is also known as 5844del5. ClinVar contains an entry for this variant (Variation ID: 51892). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131113	SCV000186043	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The c.5616_5620delAGTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 5616 to 5620, causing a translational frameshift with a predicted alternate stop codon (p.K1872Nfs*2). This pathogenic mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer, including male breast cancer (Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13:1794-9; Hernández JE et al. Hered. Cancer Clin. Pract. 2014 Apr;12(1):11; Churpek JE et al. Breast Cancer Res Treat, 2015 Jan;149:31-9; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Choi MC et al. Int J Gynecol Cancer, 2018 02;28:308-315; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Ademuyiwa FO et al. Breast Cancer Res Treat, 2019 Nov;178:151-159; Vargas E et al. Oncologist, 2019 07;24:e475-e479; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Bishop MR et al. PLoS One, 2020 Aug;15:e0238295). Of note, this alteration is also designated as 5844del5 and c.5611_5615del 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	RCV000044697	SCV000210812	pathogenic	not provided	2024-01-23	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with BRCA2-related cancers (PMID: 26287763, 20104584, 21643751, 24742220, 25726062, 27831900, 28528518, 28008555, 31325073, 35264596, 30257646); Also known as 5844del5 and 5611_5615del; This variant is associated with the following publications: (PMID: 26681312, 15533909, 24742220, 20104584, 21643751, 25726062, 28008555, 27831900, 25428789, 28528518, 28724667, 26295337, 26287763, 30128899, 29907814, 30720243, 31325073, 31415627, 31019283, 32318955, 30787465, 31825140, 35264596, 30257646)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044697	SCV000296679	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	The BRCA2 c.5616_5620del (p.Lys1872Asnfs*2) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 36329109 (2022), 32318955 (2020), 32866190 (2020), 30128899 (2018), 28528518 (2017), 28724667 (2017), 26681312 (2015), 25428789 (2015), 24742220 (2014), 20104584 (2010), 15533909 (2004)) and male breast cancer (PMID: 28008555 (2017)). The frequency of this variant in the general population, 0.000004 (1/247384 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000077356	SCV000327245	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000473703	SCV000540999	pathogenic	Familial cancer of breast	2024-03-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000077356	SCV000677687	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131113	SCV000683715	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	This variant deletes 5 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 more than 10 individuals affected with breast cancer and 1 individual affected with prostate cancer (PMID: 15533909, 20104584, 24742220, 25428789, 26681312, 27831900, 28008555, 28528518, 30257646, Color internal data). This variant has been identified in 1/247384 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.
Mendelics	RCV000195403	SCV000838816	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000077356	SCV000883123	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-11-21	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000077356	SCV000993556	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-09-11	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195403	SCV001748739	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5616_5620delAGTAA (p.Lys1872AsnfsX2) 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 4e-06 in 247384 control chromosomes. c.5616_5620delAGTAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Borg_2010, Caux-Moncoutier_2011, Hernandez_2014, Pal_2004, Pal_2016, etc.). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV001849299	SCV002107150	pathogenic	BRCA2-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	The c.5616_5620del ;p.(Lys1872Asnfs*2) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 51892; PMID: 28008555; PMID: 26287763; PMID: 26681312; PMID: 27831900; PMID: 20104584)PS4. The variant is present at low allele frequencies population databases (rs80359525 – gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Genetics Program, Instituto Nacional de Cancer	RCV000195403	SCV002515122	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131113	SCV002536152	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002477148	SCV002789231	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	2022-03-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000044697	SCV004167626	pathogenic	not provided	2023-11-22	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195403	SCV004848526	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.Lys1872AsnfsX2 variant in BRCA2 has been reported in >10 individuals with BRCA2 associated cancers (Pal 2004 PMID:15533909, Borg 2010 PMID:20104584, Hernandez 2014 PMID:24742220, Churpek 2015 PMID:25428789, Susswein 2015 PMID:26681312, Sun 2017 PMID:28724667, Cock-Rada 2018 PMID:28528518, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.005% (2/41432) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1872 and leads to a premature termination codon 2 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 for HBOC. Additionally, this variant was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51892). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant. ACMG/AMP criteria applied: PS4_Moderate, PM2_Supporting, PVS1.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV004777565	SCV005393854	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Glioma susceptibility 3; Familial prostate cancer	2024-01-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077356	SCV000109153	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077356	SCV000146646	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	RCV000195403	SCV000587781	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000044697	SCV000778688	pathogenic	not provided	2017-03-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000044697	SCV001552284	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001849299	SCV005350873	pathogenic	BRCA2-related disorder	2024-04-04	no assertion criteria provided	clinical testing	The BRCA2 c.5616_5620del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys1872Asnfs*2). This variant has been reported to be causative for hereditary breast and ovarian cancer in several publications (Pal et al. 2004. PubMedID: 15533909, reported as “5844del5”; Susswein et al. 2016. PubMed ID: 26681312, Table S1). In a large study, this variant accounted for 4% of BRCA2 mutations in African Americans (Rebbeck et al. 2018. PubMed ID: 29446198). It is documented in the gnomAD general population database in just 1 of ~247,000 alleles, and it is listed as pathogenic by the great majority of laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/51892/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.