Submissions for variant NM_007294.4(BRCA1):c.3817C>T (p.Gln1273Ter)

dbSNP: rs80357208

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112191	SCV000300023	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	RCV000048342	SCV000076355	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1273*) 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 and ovarian cancer (PMID: 17063270, 24728189, 24916970, 25682074, 29088781). This variant is also known as 3936C>T. ClinVar contains an entry for this variant (Variation ID: 55015). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162867	SCV000213354	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	clinical testing	The p.Q1273* pathogenic mutation (also known as c.3817C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3817. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in multiple hereditary breast and/or ovarian cancer families of various ethnicities (Tapia T et al. Epigenetics. Jun;3:157-63; Gallardo M et al. Breast Cancer Res. Treat. 2006 Jan;95:81-7; Peixoto A et al. Clin. Genet. 2015 Jul;88:41-8; Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat 2018 05;39(5):593-620). This alteration has also been reported in a Polish cohort of triple negative breast cancer patients (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Domagala P et al. PLoS ONE. 2015 Jun;10:e0130393). In one case control study, this mutation was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112191	SCV000325760	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000112191	SCV000564305	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000048342	SCV000839246	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003483456	SCV004231702	pathogenic	Ovarian cancer	2024-01-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112191	SCV004817742	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 16261400, 18097605, 24728189, 24916970, 25682074, 27553368, 29088781, 31125277, 33008098), and has been described as a founder variant in the Chilean population (PMID: 29088781). This variant has been identified in 11 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/) and in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001874). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112191	SCV000144886	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	RCV000048342	SCV000587350	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353484	SCV000591474	uncertain significance	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250540	SCV002520868	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only