ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3967A>T (p.Lys1323Ter) (rs80358648)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113255 SCV000300691 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131094 SCV000186024 pathogenic Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing The p.K1323* pathogenic mutation (also known as c.3967A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 3967. This changes the amino acid from a lysine to a stop codon within coding exon 10. This pathogenic mutation [designated as K1323X (4195A>T)] has been detected in at least one family diagnosed with familial pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). 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 RCV000113255 SCV000326946 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000485337 SCV000567009 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.3967A>T at the cDNA level and p.Lys1323Ter (K1323X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also reported as BRCA2 4195A>T this variant has been observed in at least one individual with breast cancer and in one individual with familial pancreatic cancer (Malone 2006, Zhen 2014). We consider BRCA2 Lys1323Ter to be pathogenic.
Counsyl RCV000113255 SCV000677678 likely pathogenic Breast-ovarian cancer, familial 2 2016-11-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485337 SCV000889034 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193724 SCV001362781 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3967A>T (p.Lys1323X) 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. The variant was absent in 225882 control chromosomes (gnomAD). c.3967A>T has been reported in the literature in individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer and also, pancreatic cancer (Rebbeck_2018, Zhen_2014, Malone_2006). These data indicate that the variant is likely to be associated with disease. Six ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic (5x) and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001193724 SCV001589617 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys1323*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with pancreatic cancer (PMID: 25356972). This variant is also known as 4195A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 51577). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113255 SCV000146350 pathogenic Breast-ovarian cancer, familial 2 1999-04-12 no assertion criteria provided clinical testing

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