Submissions for variant NM_000059.4(BRCA2):c.5614A>T (p.Lys1872Ter)

dbSNP: rs80358783

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113450	SCV000300905	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	RCV000044696	SCV000072709	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1872*) 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 and/or ovarian cancer (PMID: 17688236, 24156927). ClinVar contains an entry for this variant (Variation ID: 37979). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000212241	SCV000210357	pathogenic	not provided	2023-06-23	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; Reported in individuals with personal or family history of BRCA2-related cancers (Meyer et al., 2003; Ramus et al., 2007; Tea et al., 2014; Annala et al., 2017; Mandelker et al., 2017; Lowery et al., 2018); 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 5842A>T; This variant is associated with the following publications: (PMID: 24156927, 17688236, 26681312, 12938098, 28259476, 25525159, 28873162, 29506128, 29446198, 30787465, 32377563, 20104584)
Ambry Genetics	RCV000162926	SCV000213413	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.K1872* pathogenic mutation (also known as c.5614A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5614. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been identified in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Tea MK et al. Maturitas 2014 Jan;77:68-72; Meyer P et al. Hum. Mutat. 2003 Sep;22:259; Ramus SJ et al. Hum. Mutat. 2007 Dec;28:1207-15). It was also seen in a patient with pancreatic cancer who had a family history of breast cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 5842A>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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113450	SCV000327244	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044696	SCV000605792	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-20	criteria provided, single submitter	clinical testing	The p.Lys1872X variant in BRCA2 has been previously reported in at least 3 indiv iduals with BRCA2-associated cancers (Meyer 2003, Ramus 2007, Tea 2014) and segr egated with ovarian cancer in 1 affected relative (Ramus 2007). It was absent fr om large population studies. This nonsense variant leads to a premature terminat ion codon at position 1872, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disea se mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this va riant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Counsyl	RCV000113450	SCV000677686	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162926	SCV000903717	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212241	SCV001447151	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212241	SCV001470434	pathogenic	not provided	2020-07-21	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Baylor Genetics	RCV003473191	SCV004210545	pathogenic	Familial cancer of breast	2022-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113450	SCV000146645	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	RCV000044696	SCV000587780	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research