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

dbSNP: rs80357770

Total submissions: 8

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, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000483044	SCV000566928	pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1506_1509GAAAG and [1506 A>G; 1510insG]; This variant is associated with the following publications: (PMID: 11933205)
Ambry Genetics	RCV000569399	SCV000668485	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-02	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, designated as 1510insG and 1506A>G, has been reported in two hereditary breast and ovarian cancer families of Aboriginal descent in Canada (Liede A et al. Hum. Mutat. 2002 Apr;19(4):460). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149700	SCV003838247	pathogenic	Breast and/or ovarian cancer	2022-05-26	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000226544	SCV000587127	pathogenic	Hereditary breast 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.
PreventionGenetics, part of Exact Sciences	RCV004554649	SCV004715601	pathogenic	BRCA1-related disorder	2024-01-19	no assertion criteria provided	clinical testing	The BRCA1 c.1387_1390delinsGAAAG variant is predicted to result in a frameshift and premature protein termination (p.Lys463Glufs*17). This variant has been reported to segregate in two extended Native American kindreds with hereditary breast and ovarian cancer (HBOC; Liede et al 2002. PubMed ID: 11933205). This variant was alternatively described as two separate events occurring on the same allele (in cis): c.1506A>G and c.1510insG. This variant has not been reported in a large population database, indicating it is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/54234/). Furthermore, loss of function variants up and downstream of this position have been reported to be causative for HBOC (Human Gene Mutation Database v2020.4). This variant is interpreted as pathogenic.