ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1881_1884del (p.Ser628fs) (rs80357567)

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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) RCV000077498 SCV000299662 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077498 SCV000325163 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000479237 SCV000566154 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA1 is denoted c.1881_1884delCAGT at the cDNA level and p.Ser628GlufsX3 (S628EfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGT[delCAGT]AGAA. The deletion causes a frameshift, which changes a Serine to a Glutamic Acid at codon 628, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1881_1884delCAGT, also known as BRCA1 2000del4 using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Gayther 1999, Ang 2007, Kwong 2016). We consider this variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047618 SCV000605767 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Ser628fs variant in BRCA1 has been reported in at least 4 individuals with breast and or ovarian cancer and segregated with disease in 1 affected relative from 1 family (Gayther 1999, Breast Cancer Information (BIC) database). This va riant has also been identified in 1/33576 of Latino chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80357567); however, however, this frequency is low enough to be consistent with the freque ncy of HBOC in the general population. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 628 and leads to a premature termination codon 3 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Heterozygous l oss of function of the BRCA1 gene is an established disease mechanism in heredit ary breast and ovarian cancer (HBOC). In addition, the p.Ser628fs variant was cl assified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert pan el (ClinVar SCV000299662.2). In summary, this variant meets criteria to be class ified as pathogenic for HBOC in an autosomal dominant manner based upon the pred icted impact to the protein and low frequency in controls.
Ambry Genetics RCV000510010 SCV000607762 pathogenic Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
PreventionGenetics,PreventionGenetics RCV000479237 SCV000806902 pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing
Invitae RCV000047618 SCV000075631 pathogenic Hereditary breast and ovarian cancer syndrome 2014-06-11 no assertion criteria provided clinical testing The interpretation for this sequence variant was made by Invitae based on the ACMG guidelines. A more detailed explanation of the interpretation for this specific variant is forthcoming. This ClinVar entry will be updated at that time.
Sharing Clinical Reports Project (SCRP) RCV000077498 SCV000109297 pathogenic Breast-ovarian cancer, familial 1 2008-02-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077498 SCV000144231 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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