ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5855T>A (p.Leu1952Ter)

dbSNP: rs375064902
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Total submissions: 7
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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) RCV000031583 SCV000300942 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.
CSER _CC_NCGL, University of Washington RCV000149889 SCV000196737 likely pathogenic Hereditary breast ovarian cancer syndrome 2014-06-01 criteria provided, single submitter research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031583 SCV000327299 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563543 SCV000661266 pathogenic Hereditary cancer-predisposing syndrome 2022-03-15 criteria provided, single submitter clinical testing The p.L1952* pathogenic mutation (also known as c.5855T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 5855. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration was identified in two different cohorts unselected for cancer history in unaffected individuals and in one individual with a personal history of breast and ovarian cancers at age 29 (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Natarajan P et al. Sci Transl Med, 2016 Nov;8:364ra151). An alteration resulting in the same stop codon, p.L1952* (6083insAGTT), has also been reported in 1/294 women diagnosed with breast cancer and 0/346 female controls from the Philippines (De Leon Matsuda ML et al, Int. J. Cancer 2002 Apr; 98(4):596-603 ). In addition to the information 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000149889 SCV000758806 pathogenic Hereditary breast ovarian cancer syndrome 2023-03-18 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38002). This premature translational stop signal has been observed in individual(s) with increased risk of breast and/or ovarian cancer (PMID: 29446198). This variant is present in population databases (rs375064902, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu1952*) 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).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000149889 SCV004848522 likely pathogenic Hereditary breast ovarian cancer syndrome 2023-09-13 criteria provided, single submitter clinical testing The p.Leu1952X variant in BRCA2 has been reported in 1 individual with increased risk of breast and/or ovarian cancer (HBOC; Rebbeck 2018 PMID:29446198) and has also been reported by other clinical laboratories in ClinVar (Variant ID 38002). It was absent from large population studies (gnomAD, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1952, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. Additionally, this variant was classified as pathogenic on Sept. 08, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar: SCV000300942.2). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Sharing Clinical Reports Project (SCRP) RCV000031583 SCV000054189 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing

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