Submissions for variant NM_007294.4(BRCA1):c.1390_1391insG (p.Thr464fs)

dbSNP: rs397508867

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pathology and Molecular Medicine, Queen's University	RCV000496409	SCV000588032	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776207	SCV000911353	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1510insG in the literature. This variant also has been observed in cis with c.1387A>G (1506A>G) (PMID: 11933205). The two in cis variants, c.1387A>G and c.1390_1391insG, may be described together as 1506del4ins5 or c.1387_1390delinsGAAAG (ClinVar variation ID: 54234). This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast and ovarian cancer (PMID: 11933205, 17148771, 21324516; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003315577	SCV004018840	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV000496409	SCV004272890	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr464Serfs*16) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 11933205, 17148771). This variant is also known as 1510insG. ClinVar contains an entry for this variant (Variation ID: 54235). For these reasons, this variant has been classified as Pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496409	SCV000587129	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355685	SCV001550639	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Thr464Serfs*16 variant was identified in 2 of 5026 proband chromosomes (frequency: 0.0004) from individuals or families with ovarian cancer (Risch 2006, Zhang 2011) and in two Canadian families of aboriginal descent both with the same BRCA1 alterations (1510insG, 1506A>G)( Liede 2002). The variant was also identified in dbSNP (ID: rs397508867) as "With Pathogenic allele", ClinVar (classified as pathogenic by COGR). The variant was not identified in LOVD 3.0 and 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.1390_1391insG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 464 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.