ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1387_1390delinsGAAAG (p.Lys463fs) (rs80357770)

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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) RCV000661310 SCV000783577 pathogenic Breast-ovarian cancer, familial 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000226544 SCV000289743 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys463Glufs*17) 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 observed in individuals of Canadian aboriginal descent with a personal and family history of breast and ovarian cancers (PMID: 11933205, 17148771, 21324516). This variant is also reported as 1510insG with 1506A>G (1510insG, 1506A>G) in the literature. ClinVar contains an entry for this variant (Variation ID: 54234). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000483044 SCV000566928 pathogenic not provided 2015-06-10 criteria provided, single submitter clinical testing This mutation in BRCA1 is denoted c.1387_1390delAAAAinsGAAAG at the cDNA level and p.Lys463GlufsX17 (K463EfsX17) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets is TGGG[AAAA][GAAAG]CCTA. This variant is also known as BRCA1 1506delAAAAinsGAAAG using alternate nomenclature. The deletion and insertion causes a frameshift, which changes a Lysine to a Glutamic Acid at codon 463, and creates a premature stop codon at position 17 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.1387_1390delAAAAinsGAAAG was previously reported as two events, 1510insG and 1506A>G, in two Aboriginal Canadian families with a history of breast and ovarian cancer (Liede 2002). Based on segregation data, 1510insG and 1506A>G were suggested to be on the same chromosome (Liede 2002). we consider this variant to be pathogenic.
Ambry Genetics RCV000569399 SCV000668485 pathogenic Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing The c.1387_1390delAAAAinsGAAAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of 4 nucleotides and insertion of 5 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.K463Efs*17). This alteration has been reported (designated as 1510insG and 1506A>G) in two hereditary breast and ovarian cancer families of aboriginal descent in Canada (Liede A et al. Hum. Mutat. 2002 Apr;19(4):460). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000226544 SCV001362763 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1387_1390delinsGAAAG (p.Lys463GlufsX17) 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 was absent in 251096 control chromosomes (gnomAD). The variant, c.1387_1390delinsGAAAG, has been reported in the literature in two Native American families, where one of these families had several cases of ovarian- and breast cancer diagnosed below age 50 years (Liede_2002). Though in this family one affected family member did not carry the variant, and one unaffected family member (66 y.o.) carried it, most of the affected family members were not genotyped (Liede_2002). Another study also reported the variant in a male breast cancer patient (Bradley_2011, conference abstract). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000226544 SCV000587127 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357355 SCV001552808 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Lys463Glufs*17 variant was identified in the literature in two families of aboriginal descent both with breast and ovarian cancer (reported as 1510insG, 1506A>G) (Liede 2002). The variant was also identified in ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx, ENIGMA and COGR). The variant was not identified in dbSNP, LOVD 3.0, or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1387_1390delinsGAAAG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 463 and leads to a premature stop codon at position 479. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in BRCA1 associated cancers 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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