Submissions for variant NM_007294.4(BRCA1):c.3718C>T (p.Gln1240Ter)

dbSNP: rs80356903

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077554	SCV000282316	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048301	SCV000076314	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1240*) 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, ovarian, and endometrial cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). This variant is also known as 3837C>T. ClinVar contains an entry for this variant (Variation ID: 54978). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162866	SCV000213353	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-12	criteria provided, single submitter	clinical testing	The p.Q1240* pathogenic mutation (also known as c.3718C>T) located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3718. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in many individuals with personal and family histories of breast, ovarian, fallopian tube, and prostate cancer (Callahan MJ et al. J. Clin. Oncol. 2007 Sep;25:3985-90; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Connor JR et al. Gynecol. Oncol. 2014 Feb;132:280-6; Wang C et al. Ann. Oncol. 2015 Mar;26:523-8; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158:455-62; Cvelbar M et al. Radiol. Oncol. 2017 Jun;51(2):187-194). It has also been reported in a female patient diagnosed with advanced metastatic endometrial cancer who had a family history of melanoma, breast cancer, and prostate cancer (Kwon JS et al. Int. J. Gynecol. Cancer. 2008 May-Jun;18:546-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 3837C>T and Q1240X 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048301	SCV000271317	pathogenic	Hereditary breast ovarian cancer syndrome	2015-07-29	criteria provided, single submitter	clinical testing	The p.Gln1240X variant in BRCA1 has been reported in 2 individuals with endometr ial cancer (Kwon 2008, Conner 2014) and at least 7 individuals with breast and/o r ovarian cancer (Novakovic 2012, Wang 2015, Breast Cancer Information Core (BIC )). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1240, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA1 function is an establish ed disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) base d upon the predicted impact to the protein, presence in affected individuals, an d absence in controls.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077554	SCV000325732	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000519156	SCV000617451	pathogenic	not provided	2022-11-15	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; Observed in individuals with a personal and family history of breast and/or ovarian cancer (Balleine et al., 2010; Novakovic et al., 2012; Wang et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3837C>T; This variant is associated with the following publications: (PMID: 25525159, 25480878, 24333842, 17645508, 22923021, 17761984, 27393621, 20815029, 23397983, 26833046, 18446624, 28740454, 28888541, 28724667, 29446198, 30702160, 31825140, 32918181)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077554	SCV000743403	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000519156	SCV000887677	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	his variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with pancreatic cancer (PMID: 32918181 (2021)), ovarian cancer (PMID: 28740454 (2017)), and breast cancer (PMID: 31957001 (2020), 30702160 (2019), 28724667 (2017), 27393621 (2016), 25480878 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000077554	SCV000993553	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-22	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000162866	SCV001340476	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This variant BRCA1 c.3718C>T (also known as BRCA1 3837C>T in the literature) creates 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 endometrial, breast and ovarian cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). 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 available evidence, this variant is classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000077554	SCV001499717	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000519156	SCV002760934	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077554	SCV004216873	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077554	SCV004817759	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-19	criteria provided, single submitter	clinical testing	This variant BRCA1 c.3718C>T (also known as BRCA1 3837C>T in the literature) creates a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in individuals affected with endometrial, breast and ovarian cancer (PMID: 17645508, 22923021, 24333842, 25480878, 27393621). 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 available evidence, this variant is classified as Pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000077554	SCV005045932	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000077554	SCV000109355	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-06-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077554	SCV000144849	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	RCV000048301	SCV000587338	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077554	SCV000733621	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077554	SCV002589111	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing