ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3648dupA (p.Ser1217Ilefs) (rs80357902)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221757 SCV000273500 pathogenic Hereditary cancer-predisposing syndrome 2017-07-19 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) RCV000031116 SCV000144822 pathogenic Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000225763 SCV000219232 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-30 criteria provided, single submitter clinical testing
Color RCV000221757 SCV000683119 pathogenic Hereditary cancer-predisposing syndrome 2016-12-22 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031116 SCV000325713 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000225763 SCV000591459 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031116 SCV000299986 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 RCV000048270 SCV000108669 pathogenic Familial cancer of breast criteria provided, single submitter clinical testing Predicted to cause loss of normal protein function; Reported in association with breast and/or ovarian cancer (Peyrat 1998)
GeneDx RCV000505831 SCV000210044 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA1 c.3648dupA at the cDNA level and p.Ser1217IlefsX2 (S1217IfsX2) at the protein level. The surrounding sequence, with the base that is duplicated in brackets, is ACTT[dupA]TCTA. The duplication causes a frameshift, changing a Serine to an Isoleucine at codon 1217, and creating 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 3648dupA, also reported as BRCA1 3767dupA or 3768insA, has been reported in association with breast and/or ovarian cancer, and has been suggested to be a French Canadian founder variant (Peyrat 1998, Tonin 1998, Risch 2001, Cavallone 2010, Zhang 2011). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000225763 SCV000699051 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3648dupA (p.Ser1217Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/121296 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Multiple publications have cited this variant in affected individuals, predominantly of French origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000225763 SCV000076283 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1217Ilefs*2) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357902, ExAC 0.009%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 10866029, 21120943, 22762150). This variant is also known as 3768insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37535). 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 RCV000225763 SCV000605768 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-29 criteria provided, single submitter clinical testing The p.Ser1217fs variant in BRCA1 has been reported in 2 individuals with breast and/or ovarian cancer (Peyrat 1998, Risch 2001) and has also been identified in 1/33566 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs80357902). This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 1217 and leads to a premature termination codon 2 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the BRCA1 gene is an established disease mechanism i n hereditary breast and ovarian cancer (HBOC). In addition, this variant was cla ssified as pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert pane l (ClinVar SCV000299986.2). In summary, this variant meets criteria to be classi fied as pathogenic for HBOC in an autosomal dominant manner based upon the predi cted impact to the protein and low frequency in controls.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505831 SCV000296344 pathogenic not provided 2015-05-21 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000225763 SCV000587327 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031116 SCV000053714 pathogenic Breast-ovarian cancer, familial 1 2009-10-09 no assertion criteria provided clinical testing

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