Submissions for variant NM_000059.4(BRCA2):c.4588A>T (p.Lys1530Ter)

dbSNP: rs80358692

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077329	SCV000300769	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	RCV000044447	SCV000072460	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1530*) 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 (PMID: 25452441, 26681312). ClinVar contains an entry for this variant (Variation ID: 51678). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000212238	SCV000210339	pathogenic	not provided	2022-01-19	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 in individuals with breast cancer (Couch 2015, Susswein 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4816A>T; This variant is associated with the following publications: (PMID: 25452441, 26681312, 28152038, 29446198, 31640893, 30787465)
Ambry Genetics	RCV000162921	SCV000213408	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The p.K1530* pathogenic mutation (also known as c.4588A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4588. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer and in 1 breast cancer patient out of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Couch FJ et al. J Clin Oncol. 2015 Feb 1;33(4):304-11; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077329	SCV000327057	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077329	SCV000488190	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044447	SCV000605789	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-15	criteria provided, single submitter	clinical testing	The p.Lys1530X variant in BRCA2 has been reported in at least 9 individuals with BRCA2-associated cancers (Susswein 2015, Couch 2015, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 1530, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ova rian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212238	SCV000889053	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25452441 (2015), 26681312 (2016)), ovarian cancer (PMID: 28888541 (2017)), and prostate cancer (PMID: 31640893 (2020)). It was also reported in healthy individuals (PMID: 32906206 (2020)). Additionally, this variant was reported in a large global study of BRCA1/BRCA2 positive families (PMID: 29446198 (2018)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162921	SCV000903414	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	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 three individuals affected with breast cancer (PMID: 25452441, 26681312, Color internal data) and one individual affected with prostate cancer (PMID: 31640893). This variant has been identified in 5 families among the CIMBA participants (PMID: 29446198). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044447	SCV001442628	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4588A>T (p.Lys1530X) 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 was absent in 250310 control chromosomes (gnomAD). c.4588A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or prostate cancer (Couch_2015, Rebbeck_2018, Reimers_2019). 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. Nine ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic (8x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000077329	SCV001469050	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-02	criteria provided, single submitter	clinical testing	This nonsense variant has been reported in multiple unrelated individuals affected with hereditary breast and ovarian cancer. It results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. This variant is absent in a large population database and has an entry in ClinVar. We consider c.4588A>T to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212238	SCV001474557	pathogenic	not provided	2020-06-05	criteria provided, single submitter	clinical testing	The BRCA2 c.4588A>T; p.Lys1530Ter variant (rs80358692) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Couch 2015, Rebbeck 2018), and is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 66346). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant 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 Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212238	SCV002010364	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001762137	SCV003835696	pathogenic	Familial cancer of breast	2022-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212238	SCV004238511	likely pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077329	SCV000109126	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077329	SCV000146454	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044447	SCV000587717	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research