ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4648G>T (p.Glu1550Ter) (rs80358695)

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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) RCV000113326 SCV000300776 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044460 SCV000072473 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1550*) 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 observed in two siblings affected with Fanconi anemia (PMID: 14670928). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113326 SCV000327066 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571951 SCV000665039 pathogenic Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing The p.E1550* pathogenic mutation (also known as c.4648G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4648. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. Designated as 4876G>T, this mutation has been seen in trans with another BRCA2 alteration in a patient with Fanconi anemia (Hirsch B et al. Blood. 2004 Apr;103:2554-9). This mutation has also been reported in a worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). In additional 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.
Integrated Genetics/Laboratory Corporation of America RCV000044460 SCV000916974 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4648G>T (p.Glu1550X) 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 (eg.c.4707C>A (p.Tyr1569X), c.4712_4713delAG (p.Glu1571fsX3), c.4808dupA (p.Asn1603fsX6)). The variant was absent in 245688 control chromosomes (in gnomAD). The variant, c.4648G>T, has been reported in the literature in patients affected with Fanconi Anemia (Hirsch 2004) in compound heterozygosity with the variant c.7529T>C (p.Leu2510Pro). These data indicate that the variant may be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, demonstrating the absence of BRCA2 in cells derived from patients, together with a marked chromosome instability and hypersensitivity to cross-linking agents, consistent with the diagnosis of Fanconi Anemia. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000009935 SCV000030156 pathogenic Fanconi anemia, complementation group D1 2004-04-01 no assertion criteria provided literature only
Breast Cancer Information Core (BIC) (BRCA2) RCV000113326 SCV000146461 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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