Submissions for variant NM_007294.4(BRCA1):c.4609C>T (p.Gln1537Ter)

dbSNP: rs80357229

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112363	SCV000300142	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112363	SCV000326007	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000479214	SCV000564740	pathogenic	not provided	2018-05-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4609C>T at the cDNA level and p.Gln1537Ter (Q1537X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as c.4728C>T, has been observed in association with breast and/or ovarian cancer (Ozcelik 2003, Yassaee 2016) and is considered pathogenic.
Ambry Genetics	RCV000509797	SCV000608084	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The p.Q1537* pathogenic mutation (also known as c.4609C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4609. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation, designated as 4728C>T, has been reported in one individual diagnosed with invasive breast cancer (Ozcelik H et al. J Med Genet. 2003 Aug;40(8):e91). This mutation has also been identified in a patient of Iranian ethnicity with both a personal and family history of breast and/or ovarian cancers (Yassaee VR et al. Asian Pac J Cancer Prev. 2016;17(S3):149-53). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000112363	SCV000746293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV000496357	SCV001588703	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55237). This variant is also known as p.Q1537X (c.4728C>T). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian (PMID: 12920083, 27165220, 30078507). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1537*) 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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112363	SCV000145127	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112363	SCV000297613	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-02-08	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496357	SCV000587412	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000479214	SCV001552263	uncertain significance	not provided		no assertion criteria provided	clinical testing