Submissions for variant NM_007294.4(BRCA1):c.4372C>T (p.Gln1458Ter)

dbSNP: rs80356932

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)	RCV000112328	SCV000300109	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.
Ambry Genetics	RCV000131884	SCV000186939	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.Q1458* pathogenic mutation (also known as c.4372C>T), located in coding exon 12 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4372. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Rostagno P et al. J Hum Genet. 2003;48(7):362-6; Kwong A et al. Breast Cancer Res. Treat. 2009; 117:683-6; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Li JY et al. Int J Cancer, 2019 01;144:281-289; Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000112328	SCV000325941	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131884	SCV000683177	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 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 individuals affected with breast and/or ovarian cancer (PMID: 19353265, 21120943, 24578176, 25480878). 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.
GeneDx	RCV000657617	SCV000779359	pathogenic	not provided	2018-09-18	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4372C>T at the cDNA level and p.Gln1458Ter (Q1458X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast and/or ovarian cancer (Tang 1999, Caux-Moncoutier 2011, Kang 2014, Wang 2015) and is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381001	SCV001579249	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 55183). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 28724667, 29446198, 29752822, 30078507, 30702160). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1458*) 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).
Baylor Genetics	RCV000112328	SCV004215201	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657617	SCV004224849	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate, PVS1
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112328	SCV000145077	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657617	SCV000591513	uncertain significance	not provided		no assertion criteria provided	clinical testing