Submissions for variant NM_007294.4(BRCA1):c.1480C>T (p.Gln494Ter)

dbSNP: rs80357010

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000030996	SCV000299605	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	RCV000047490	SCV000075503	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln494*) 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: 10866029, 25066507, 25863477, 26187060). This variant is also known as 1599C>T. ClinVar contains an entry for this variant (Variation ID: 37415). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000030996	SCV000195891	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000223308	SCV000275584	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	clinical testing	The p.Q494* pathogenic mutation (also known as c.1480C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1480. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been detected in multiple individuals with personal and/or family histories suggestive of hereditary breast and ovarian cancer (HBOC) syndrome (Peyrat JP et al. Eur. J. Cancer Prev. 1998 Feb;7 Suppl 1:S7-12; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Lesueur F et al. Front Oncol, 2018 Oct;8:490). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000030996	SCV000296334	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-05-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030996	SCV000325078	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000030996	SCV000487901	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047490	SCV000605760	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-11	criteria provided, single submitter	clinical testing	The p.Gln494X variant in BRCA1 has been identified in >5 individuals with BRCA1- associated cancers (Peyrat 1998, Kim 2012, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This nonsense variant le ads to a premature termination codon at position 494, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 ge ne is an established disease mechanism in hereditary breast and ovarian cancer ( HBOC). Furthermore, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000299605.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autoso mal dominant manner.
GeneDx	RCV000657593	SCV000779331	pathogenic	not provided	2022-02-28	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; 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 1599C>T; This variant is associated with the following publications: (PMID: 25066507, 30430080, 26187060, 10866029, 26295337, 22798144, 16267036, 25863477, 28205045, 25256924, 29673794, 30702160, 32341426, 31825140, 30078507, 29446198, 25525159, Bahsi2020[case report], 33718561)
Color Diagnostics, LLC DBA Color Health	RCV000223308	SCV001351492	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-14	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 individuals affected with breast and ovarian cancer (PMID: 10866029, 22798144, 25066507, 25256924, 25863477, 26187060, 28205045). 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. Based on the available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000657593	SCV001446579	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047490	SCV002500754	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1480C>T (p.Gln494X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251190 control chromosomes. c.1480C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000657593	SCV004041997	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Baylor Genetics	RCV000030996	SCV005058247	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657593	SCV005413238	pathogenic	not provided	2024-04-15	criteria provided, single submitter	clinical testing	PM2, PM5_strong, PVS1
Sharing Clinical Reports Project (SCRP)	RCV000030996	SCV000053588	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030996	SCV000144107	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	RCV000047490	SCV000587140	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research