Submissions for variant NM_000059.4(BRCA2):c.6486_6489del (p.Lys2162fs)

dbSNP: rs80359598

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031630	SCV000282428	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	RCV000044967	SCV000072980	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2162Asnfs*5) 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 (rs770263702, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 19949876, 20736950, 23479189, 24145998, 24156927, 25586199, 25896959, 26026974, 26360800, 26681312). This variant is also known as 6710delACAA or 6714delACAA. ClinVar contains an entry for this variant (Variation ID: 38048). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131034	SCV000185964	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-31	criteria provided, single submitter	clinical testing	The c.6486_6489delACAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6486 to 6489, causing a translational frameshift with a predicted alternate stop codon (p.K2162Nfs*5). This alteration has been reported in multiple cohorts of individuals and families with early-onset or familial breast cancer (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Thomassen M et al. Acta. Oncol. 2008;47:772-7; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Sambiasi D et al. Oncol. Rep. 2014 Jan;31:365-9; D'Argenio V et al. Clin. Chim. Acta. 2015 Jun;446:221-5; Hoyer J et al. BMC Cancer. 2018 Sep;18:926; Millan Catalan O et al. Cancers (Basel). 2019 Aug;11:; Abdel-Razeq H et al. Sci Rep. 2021 07;11:14906), as well as patients with prostate, ovarian, and pancreatic cancer diagnoses (Edwards SM et al. Am. J. Hum. Genet. 2003 Jan;72:1-12; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Roed Nielsen H et al. Acta. Oncol. 2016 Sep;55:38-44; Pishvaian MJ et al. Br J Cancer. 2017 Apr;116:1021-1026; Li A et al. Gynecol Oncol. 2018 10;151:145-152). Of note, this alteration is also designated as 6714del4 and 6710delACAA 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	RCV000212249	SCV000210782	pathogenic	not provided	2021-08-19	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; 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; This variant is associated with the following publications: (PMID: 33587123, 32318955, 26689913, 29625052, 31957001, 31454914, 30322717, 30702160, 28176296, 30078507, 30720243, 28724667, 29084914, 29339979, 11389159, 27376475, 28127413, 27225819, 28291774, 26026974, 26681312, 10660329, 10969800, 16684319, 25371446, 26360800, 25452441, 24145998, 18465347, 23479189, 20736950, 12474142)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212249	SCV000296740	pathogenic	not provided	2023-11-08	criteria provided, single submitter	clinical testing	The BRCA2 c.6486_6489del (p.Lys2162Asnfs*5) 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 (PMIDs: 36292577 (2022), 35864222 (2022), 34290354 (2021), 32862574 (2020), 31957001 (2020), 30257646 (2018), 29339979 (2018), 26681312 (2015), 23479189 (2013), 21847643 (2012)), ovarian cancer (PMIDs: 32872764 (2020), 29084914 (2018), 23479189 (2013)), and prostate cancer (PMIDs: 33804961 (2021), 26360800 (2016), 12474142 (2003), 10969800 (2000)). The frequency of this variant in the general population, 0.0000086 (2/232332 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	RCV000031630	SCV000327441	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031630	SCV000577964	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044967	SCV000586968	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031630	SCV000605648	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031630	SCV000677693	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131034	SCV000683787	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 6714delACAA, 6714del4, 6710delACAA and 6710del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in over 10 individuals affected with breast and/or ovarian cancer (PMID: 10978364, 11389159, 18694767, 20104584, 23479189, 24145998, 25371446, 25452441, 25586199, 26026974, 26360800, 26681312, 29084914, 30702160, 33471991; Leiden Open Variation Database DB-ID BRCA2_000162) and is reported as a recurrent mutation in Danish hereditary breast and ovarian cancer families (PMID: 18465347). This variant also has been reported in one individual each affected with pancreatic and prostate cancer (PMID: 10969800, 28291774). This variant has been identified in 2/232332 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044967	SCV000694978	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-08	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6486_6489delACAA (p.Lys2162Asnfs) variant (alternatively also known as 6714del4 and 6710delACAA) results in deletion of 4 nucleotides from exon 11 of the BRCA2 mRNA, causing a frameshift that creates a premature stop codon. This is predicted to cause a truncated or absent (due to nonsense mediated decay) BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.6591_6592delTG (p.Glu2198fs), c.7069_7070delCT (p.Leu2357fs), etc.) This variant was found in the large and broad control populations from ExAC in 2/ 118868 chromosomes at a frequency of 0.0000168, which does not exceed maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in numerous HBOC patients, including male breast cancer and prostate cancer patients (Plaschke_2000, Bergthorsson_2001, Thomassen_2008, Tommasi_2008, Alsop_2012, de Juan_2015, Nielsen_ 2017) and also in a female patient with pancreatic cancer (Pishvaian_2017). In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University	RCV000768561	SCV000899224	pathogenic	Breast carcinoma	2019-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002473	SCV001160421	pathogenic	not specified	2019-03-21	criteria provided, single submitter	clinical testing	The BRCA2 c.6486_6489delACAA; p.Lys2162fs variant (rs80359598) has been reported in individuals affected with breast (de Juan Jimenez 2013), ovarian (Li 2018, Shi 2017), or prostate cancer (Edwards 2003, Edwards 2010). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 38048), and it is observed on only two chromosomes (2/232332 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting four nucleotides, so it 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: de Juan Jimenez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013; 12(4):767-77. Edwards S et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003; 72(1):1-12. Edwards S et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010; 103(6):918-24. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152. Shi T et al. BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer. Int J Cancer. 2017 May 1;140(9):2051-2059.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031630	SCV001428530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-07-30	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212249	SCV001447470	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212249	SCV001449811	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000031630	SCV002506806	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-06-11	criteria provided, single submitter	clinical testing	The heterozygous c.6486_6489del (p.Lys2162AsnfsTer5) frameshift variant identified in exon 11 (of 27) of the BRCA2 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in multiple unrelated individuals affected with BRCA2-associated disorders [PMID: 10660329; PMID:12474142; PMID:23479189; PMID:26360800; PMID:29339979]. This variant has also been reported as Pathogenic in ClinVar by multiple independent laboratories (Variation ID: 38048). The variant has 0.00001972 allele frequency in the gnomAD(v3) database (3 out of 152128 heterozygous alleles, no homozygotes) indicating it is not a common benign variant in the populations represented in that database. Based on the available evidence, the heterozygousc.6486_6489del (p.Lys2162AsnfsTer5) frameshift variant identified in the BRCA2 gene is reported as Pathogenic.
Sema4, Sema4	RCV000131034	SCV002536240	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212249	SCV002551858	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000031630	SCV002579826	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212249	SCV003816157	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473203	SCV004211852	pathogenic	Familial cancer of breast	2023-10-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212249	SCV004704430	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044967	SCV004847639	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-20	criteria provided, single submitter	clinical testing	The p.Lys2162AsnfsX5 variant in BRCA2 has been reported in greater than 30 individuals with BRCA2-associated cancer (de Juan Jimenez 2013, Edwards 2003, Edwards 2010, Labidi-Galy 2018, Li 2018, Nielsen 2016, Sun 2017; Breast Information Core database). It has been identified in 1/26026 South Asian and 1/29656 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38048). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2162 and leads to a premature termination codon 5 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031630	SCV005045976	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	RCV000212249	SCV005199552	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803062	SCV005424536	pathogenic	BRCA2-related cancer predisposition	2024-06-09	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 6714delACAA, 6714del4, 6710delACAA and 6710del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in over 10 individuals affected with breast and/or ovarian cancer (PMID: 10978364, 11389159, 18694767, 20104584, 23479189, 24145998, 25371446, 25452441, 25586199, 26026974, 26360800, 26681312, 29084914, 30702160, 33471991; Leiden Open Variation Database DB-ID BRCA2_000162) and is reported as a recurrent mutation in Danish hereditary breast and ovarian cancer families (PMID: 18465347). This variant also has been reported in one individual each affected with pancreatic and prostate cancer (PMID: 10969800, 28291774). This variant has been identified in 2/232332 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.
Sharing Clinical Reports Project (SCRP)	RCV000031630	SCV000054237	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-22	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031630	SCV000146871	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	RCV000044967	SCV000587852	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001271057	SCV001451876	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031630	SCV002588904	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000031630	SCV003927853	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541044	SCV004777344	pathogenic	BRCA2-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The BRCA2 c.6486_6489delACAA variant is predicted to result in a frameshift and premature protein termination (p.Lys2162Asnfs*5). This variant has been reported in patients with breast, ovarian, and prostate cancer (reported as 6710delACAA in Edwards et al. 2003. PubMed ID: 12474142; reported as 6486delACAA in Edwards et al. 2010. PubMed ID: 20736950; De Juan Jimenez et al. 2013. PubMed ID: 23479189; Table S2, Labidi-Galy et al. 2018. PubMed ID: 29084914). This variant is reported in 0.0038% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by several submitters to ClinVar, including a ClinGen Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38048/). This variant is interpreted as pathogenic.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031630	SCV005061337	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control