Submissions for variant NM_000059.4(BRCA2):c.6037A>T (p.Lys2013Ter)

dbSNP: rs80358840

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031597	SCV000300972	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.
Invitae	RCV000044827	SCV000072840	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2013*) 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 cancer, ovarian cancer, fallopian tube cancer, and prostate cancer (PMID: 11802209, 11897832, 17513806, 22006311, 24504028, 24728189, 25111659). This variant is also known as 6265A>T. ClinVar contains an entry for this variant (Variation ID: 38016). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131111	SCV000186041	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	The p.K2013* pathogenic mutation (also known as c.6037A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6037. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been described in multiple breast, ovarian, pancreatic, and prostate cancer patients and families (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Maier C et al. Prostate. 2014 Oct;74:1444-51; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333; Dudley B et al. Cancer. 2018 Apr;124:1691-1700). Of note, this alteration is also designated as 6265A>T in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Counsyl	RCV000031597	SCV000220422	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-06-17	criteria provided, single submitter	literature only
GeneDx	RCV000217667	SCV000278866	pathogenic	not provided	2023-07-06	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; 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 6265A>T; This variant is associated with the following publications: (PMID: 22006311, 24784157, 21913181, 32438681, 29922827, 24504028, 25896959, 11802209, 25111659, 25525159, 24728189, 27225637, 19941162, 16168123, 28127413, 23961350, 28259476, 11897832, 17513806, 27463008, 25085752, 29360161, 29084914, 30128899, 26556299, 30487452, 29061375, 29446198, 29625052, 26689913, 31447099, 31514334, 30787465, 35264596, 31892343)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217667	SCV000296643	pathogenic	not provided	2019-10-03	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in cases of breast, ovarian, prostate, and fallopian tube cancer, and described as deleterious in the published literature (PMID: 24728189 (2014), 25111659 (2014), 21913181 (2012), 22006311 (2011), 11897832 (2002), 11802209 (2002)). 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	RCV000031597	SCV000327336	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506478	SCV000602814	pathogenic	not specified	2016-11-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044827	SCV000605782	pathogenic	Hereditary breast ovarian cancer syndrome	2015-07-30	criteria provided, single submitter	clinical testing	The p.Lys2013X variant has been reported in >20 individuals with BRCA2-associate d cancers (Meindl 2002, Hamann 2002, Wappenschmidt 2005, Machado 2007, Walsh 201 1, Litton 2012, Solano 2012, Cunningham 2014, Maier 2014, Breast Cancer Informat ion Core (BIC) database). It was absent from large control studies. This nonsens e variant leads to a premature termination codon at position 2013, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 funct ion is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic f or HBOC in an autosomal dominant manner based upon the predicted impact to the p rotein and presence in affected individuals.
Color Diagnostics, LLC DBA Color Health	RCV000131111	SCV000688963	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 11897832, 16168123, 17513806, 21913181, 22006311, 23961350, 24504028, 24728189, 25111659, 24728189, 29084914, 29360161, 32380732, 32438681), pancreatic cancer (PMID: 29360161), or prostate cancer (PMID: 25111659). 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.
GeneKor MSA	RCV000044827	SCV000693575	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Lysine to a Termination codon at amino acid residue 2013 of the BRCA2 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as 6265A>T in the literature and has been reported in patients with breast, ovarian, fallopian tube and prostate cancer (PMID: 11802209, 11897832, 22006311, 25111659). The mutation database ClinVar contains entries for this variant (Variation ID: 38016).
Mendelics	RCV000044827	SCV000838831	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031597	SCV000839935	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-23	criteria provided, single submitter	clinical testing	This c.6037A>T (p.Lys2013*), variant in exon 11 of the BRCA2 gene creates a stop codon which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 17513806, 21913181, 22006311, 23961350, 24504028, 25111659). Therefore, the c.6037A>T (p.Lys2013*) variant in the BRCA2 gene is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044827	SCV000918981	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6037A>T (p.Lys2013X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 253864 control chromosomes. c.6037A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Meindl_2002, Machado_2007, Song_2014, Litton_2011, Tarabeux_2014, Solano_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11802209, 23961350, 21913181, 23942203, 17513806, 24728189, Solano et al.,(2016) Oncotarget). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic, including 1 expert panel (ENIGMA). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000217667	SCV002020288	pathogenic	not provided	2019-05-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000217667	SCV002063094	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473197	SCV004211812	pathogenic	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031597	SCV004846687	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 or ovarian cancer (PMID: 11802209, 11897832, 16168123, 17513806, 21913181, 22006311, 23961350, 24504028, 24728189, 25111659, 24728189, 29084914, 29360161, 32380732, 32438681), pancreatic cancer (PMID: 29360161), or prostate cancer (PMID: 25111659). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031597	SCV000054204	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031597	SCV000146755	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	RCV000044827	SCV000587818	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research