Submissions for variant NM_007294.4(BRCA1):c.928C>T (p.Gln310Ter)

dbSNP: rs397509338

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)	RCV000257439	SCV000323934	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000257439	SCV000326464	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657623	SCV000779366	pathogenic	not provided	2015-12-22	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.928C>T at the cDNA level and p.Gln310Ter (Q310X) 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, also published as BRCA1 c.1047C>T using alternate nomenclature, has been reported in association with breast and ovarian cancer (Wang 2000, Kim 2006, Seong 2009, Tang 2001), and is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416963	SCV001360774	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.928C>T (p.Gln310X) 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 251376 control chromosomes (gnomAD). c.928C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. A database, UMD, reports the variant to co-occur with another pathogenic BRCA1 variant, c.2433delC (p.Lys812ArgfsX3). Four ClinVar submissions including an expert panel, ENIGMA (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000416963	SCV001588885	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55758). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11059339, 17100994, 22798144, 29020732). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln310*) 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).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657623	SCV002009415	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371890	SCV002686872	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	clinical testing	The p.Q310* pathogenic mutation (also known as c.928C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 928. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been detected in multiple breast and/or ovarian cancer patients (Wang PH et al. Jpn J Clin Oncol, 2000 Aug;30:343-8; Seong MW et al. Clin Genet, 2009 Aug;76:152-60; Meisel C et al. Arch Gynecol Obstet, 2017 May;295:1227-1238; Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Choi MC et al. Cancer Res Treat, 2020 Apr;52:634-644; Chao A et al. J Gynecol Oncol, 2020 May;31:e24; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 1047C>T and 1047 (CAG to TAG) in published literature. 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.
Color Diagnostics, LLC DBA Color Health	RCV002371890	SCV004361088	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-06	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 affected with breast and/or ovarian cancer (PMID: 11059339, 11433401, 17100994, 22438049, 22798144, 29020732, 30982232, 30350268, 30309222, 31958182) and has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001915). 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.
Veritas Genetics, Veritas Genetics	RCV000416963	SCV000494572	pathogenic	Hereditary breast ovarian cancer syndrome	2016-06-28	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000257439	SCV002589075	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing