ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4552del (p.Glu1518fs) (rs398122783)

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Total submissions: 12
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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) RCV000077730 SCV000300762 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 RCV000129446 SCV000184216 pathogenic Hereditary cancer-predisposing syndrome 2018-12-03 criteria provided, single submitter clinical testing The c.4552delG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 4552, causing a translational frameshift with a predicted alternate stop codon (p.E1518Nfs*25). This alteration has been previously described in two different population-based North American breast cancer cohorts (Malone KE et al. Cancer Res. 2006 Aug;66:8297-308; Lee E et al. Breast Cancer Res. 2008 Feb;10:R19). Of note, this alteration has been designated 4780delG in the published literature. 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.
Invitae RCV000204632 SCV000261349 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1518Asnfs*25) 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 the literature in individuals affected with breast cancer (PMID: 16912212, 18284688). This variant is also known as 4780delG in the literature. ClinVar contains an entry for this variant (Variation ID: 91822). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505840 SCV000296694 pathogenic not provided 2015-03-31 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077730 SCV000327052 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077730 SCV000489256 likely pathogenic Breast-ovarian cancer, familial 2 2016-09-11 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000077730 SCV000839928 pathogenic Breast-ovarian cancer, familial 2 2017-11-10 criteria provided, single submitter clinical testing The c.4552delG frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with breast cancer [PMID 16912212, 18284688]. A nonsense variant at the same position, c.4552G>T (p.Glu1518*), has also been reported in individuals with breast and ovarian cancer (PMID: 11897832). This variant in the BRCA2 gene is classified as pathogenic.
Color Health, Inc RCV000129446 SCV000903715 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000204632 SCV001372444 pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4552delG (p.Glu1518AsnfsX25) 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 allele was found at a frequency of 4e-06 in 251858 control chromosomes. c.4552delG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Malone_2006, Lee_2008, Meindl_2002, Rebbeck_2018, Friebel_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. Seven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=7)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077730 SCV000109533 pathogenic Breast-ovarian cancer, familial 2 2012-02-26 no assertion criteria provided clinical testing
Pathway Genomics RCV000077730 SCV000207340 pathogenic Breast-ovarian cancer, familial 2 2014-11-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353452 SCV000591908 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Glu1518AsnfsX25 deletion variant was identified in the literature in an individual with breast cancer (Lee 2008); however, the variant was not identified in any of the databases searched, including dbSNP, HGMD, UMD, COSMIC, BIC, and LOVD. The p.Glu1518AsnfsX25 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1518 and leads to a premature stop codon 25 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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