ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.143del (p.Met48fs) (rs80357637)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129404 SCV000184173 pathogenic Hereditary cancer-predisposing syndrome 2016-06-09 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)
Breast Cancer Information Core (BIC) (BRCA1) RCV000030993 SCV000144462 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129404 SCV000911646 pathogenic Hereditary cancer-predisposing syndrome 2017-11-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030993 SCV000325070 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000030993 SCV000299413 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000657256 SCV000778986 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.143delT at the cDNA level and p.Met48SerfsX2 (M48SfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGCA[delT]GCTG. The deletion causes a frameshift which changes a Methionine to a Serine at codon 48, and creates a premature stop codon at position 2 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.143delT, also defined as BRCA1 262delT using alternate nomenclature, has been observed in at least one woman with ovarian cancer whose tumor studies revealed loss of heterozygosity of the wildtype allele, suggesting this variant may have been involved in tumorigenesis (Dworkin 2009). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000047475 SCV000918698 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.143delT (p.Met48SerfsX2) 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 (e.g. c.178C>T (p.Gln60X), c.188T>A (p.Leu63X), and c.220C>T (p.Gln74X)). The variant was absent in 114726 control chromosomes (ExAC). The variant, c.143delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins 2005, Spearman 2008, Foley 2014). 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. Five 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.
Invitae RCV000047475 SCV000075488 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met48Serfs*2) in the BRCA1 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 an individual affected with ovarian cancer (PMID: 26023681). This variant is also known as 262delT in the literature. ClinVar contains an entry for this variant (Variation ID: 37412). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047475 SCV000605747 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Met48fs variant in BRCA1 has been reported in at least 6 individuals with BRCA1-associated cancers (Foley 2015, Breast Cancer Information Core (BIC) datab ase) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 48 and leads to a premature termination codon 2 amino acids downstream. Heterozygous loss of function of the BRCA1 gene is an established disease mecha nism in individuals with hereditary breast and ovarian cancer (HBOC). Additional ly, the p.Met48fs variant was classified as Pathogenic on September 8, 2016 by t he ClinGen-approved ENIGMA expert panel (ClinVar SCV000299413.2). In summary, th is variant meets our criteria to be classified as pathogenic for HBOC in an auto somal dominant manner.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047475 SCV000587020 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000030993 SCV000053585 pathogenic Breast-ovarian cancer, familial 1 2012-08-30 no assertion criteria provided clinical testing

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