Submissions for variant NM_007294.4(BRCA1):c.505C>T (p.Gln169Ter)

dbSNP: rs80357133

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112722	SCV000299468	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048752	SCV000076765	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 7493024, 16267036). This sequence change creates a premature translational stop signal at codon 169 (p.Gln169*). It is expected to result in an absent or disrupted protein product.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112722	SCV000326125	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775189	SCV000909409	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 of the BRCA1 gene, creating a premature translation stop signal. 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 individuals affected with breast/ovarian cancer (PMID: 7493024, 23877192). 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.
Baylor Genetics	RCV000112722	SCV004216962	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775189	SCV005100928	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing	The p.Q169* pathogenic mutation (also known as c.505C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 505. This changes the amino acid from a glutamine to a stop codon within coding exon 6. 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.
GeneDx	RCV004700341	SCV005201808	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1995; Wen et al., 2018; Momozawa et al., 2018); Published functional studies suggest a damaging effect: reduced E3 ubiquitin ligase activity (Starita et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 624C>T; This variant is associated with the following publications: (PMID: 25525159, 7493024, 25823446, 32295079, 20104584, 29446198, 30287823, 34680387, 32377563, 31209999, 28993434, 16267036)
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112722	SCV000145602	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048752	SCV000587057	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353667	SCV000591274	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Gln169X has been identified in 1 out of 120 proband chromosomes (frequency 0.008) in an individual with a familial breast and ovarian cancer phenotype, however no controls were included in this study (Gayther 1995). It is listed in dbSNP database coming from a “clinical source” (ID#: rs80357133) where no frequency information was available. The p.Gln169X variant leads to a premature stop codon at position 169, which is predicted to cause a truncated or absent protein product and loss of function. Loss of BRCA1 function is an established disease mechanism in familial breast and ovarian cancer syndromes. In addition, this variant is listed 5 times in BIC database as a clinically important mutation. In summary, based on the information above, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735469	SCV000863606	pathogenic	Breast and/or ovarian cancer	2015-05-25	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000735469	SCV001451843	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112722	SCV004244166	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing