Submissions for variant NM_007294.4(BRCA1):c.241C>T (p.Gln81Ter)

dbSNP: rs80357350

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)	RCV000112105	SCV000299430	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	RCV000047834	SCV000075847	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-08	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 (PMID: 20104584). This variant has been reported in a family affected with breast cancer or ovarian cancer (PMID: 15382066). This variant is also known as c.360C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54565). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln81*) in the BRCA1 gene. 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	RCV000112105	SCV000325352	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112105	SCV000564299	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763008	SCV000893453	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001015488	SCV001176327	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The p.Q81* pathogenic mutation (also known as c.241C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 241. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been reported in multiple families with hereditary breast and/or ovarian cancer (Oros KK et al. Int. J. Cancer 2004 Nov;112(3):411-9; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). Of note, this mutation is also designated as 360C>T in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321493	SCV004026823	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000112105	SCV004211771	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-03-08	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112105	SCV000144777	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047834	SCV000587041	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353463	SCV000591253	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Gln81X variant was identified in 1 of 338 proband chromosomes (frequency: 0.003) from individuals or families with Breast and or Ovarian cancer (Oros, 2004). The variant was also identified in dbSNP (ID: rs80357350) “With pathogenic allele”, HGMD, ClinVar database (sighted by BIC and invitae), the BIC database (3X with class 5 clinical importance), and UMD (5X as a causal variant). The p.Gln81X variant leads to a premature stop codon at position 81, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735472	SCV000863609	pathogenic	Breast and/or ovarian cancer	2000-09-06	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112105	SCV001238526	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro