Submissions for variant NM_007294.4(BRCA1):c.3607C>T (p.Arg1203Ter)

gnomAD frequency: 0.00001  dbSNP: rs62625308

Total submissions: 50

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019240	SCV000282311	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	RCV000048251	SCV000076264	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1203*) 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 present in population databases (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894493, 21324516, 22006311, 22752604, 24010542). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131818	SCV000186873	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-27	criteria provided, single submitter	clinical testing	The p.R1203* pathogenic mutation (also known as c.3607C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3607. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported in multiple families with breast and/or ovarian cancer across various ethnicities (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Hirasawa A et al. Jpn. J. Clin. Oncol. 2014 Jan;44:49-56; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this alteration is also designated as 3726C>T 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.
GeneDx	RCV000159978	SCV000210150	pathogenic	not provided	2021-08-18	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 several individuals with a personal and/or family history of BRCA1-related cancers (Friedman 1994, Walsh 2011, Zhang 2011, Konstantopoulou 2014, Sung 2017); 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 (Lek 2016); Also known as 3726C>T; This variant is associated with the following publications: (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159978	SCV000296328	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	The BRCA1 c.3607C>T (p.Arg1203*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in many individuals with breast and/or ovarian cancer in the published literature (PMIDs: 7894493 (1994), 24218521 (2014), 24010542 (2014), 22752604 (2012), 22006311 (2011), 21553119 (2012), 21324516 (2011), 20104584 (2010), 12655560 (2003), 30702160 (2019), 30555256 (2018), and 28993434 (2018)). The frequency of this variant in the general population, 0.000012 (3/251014 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000239343	SCV000296797	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 1203, p.(Arg1203*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families affected by breast and ovarian cancer and was shown to segregate with disease in one family (PMID: 21324516, 22006311). This sequence change is also known as 3726C>T in the literature. This mutation has been described in the mutation database ClinVar (Variation ID:17671).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735444	SCV000324835	pathogenic	Breast and/or ovarian cancer	2016-03-13	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019240	SCV000325699	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000019240	SCV000488004	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131818	SCV000537658	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-24	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 observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 chromosomes 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.
Baylor Genetics	RCV000239343	SCV000540941	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000019240	SCV000564385	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-11	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000048251	SCV000588046	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048251	SCV000605742	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Arg1203X variant in BRCA1 has been reported in >40 individuals with BRCA1-associated cancers (Friedman 1994, Manguoglu 2003, Walsh 2011, Solano 2012, Kim 2012, Juwle 2012, Couch 2015, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/17194 East Asian and 2/111402 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs62625308). This nonsense variant leads to a premature termination codon at position 1203, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282311.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000019240	SCV000744631	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677815	SCV000803975	pathogenic	Ovarian cancer	2017-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048251	SCV000918688	pathogenic	Hereditary breast ovarian cancer syndrome	2019-08-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3607C>T (p.Arg1203X) 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 allele was found at a frequency of 1.2e-05 in 251014 control chromosomes. c.3607C>T has been reported in the literature in numerous individuals affected with hereditary or early-onset breast and/or ovarian cancer (ie. Friedman_1994, Meindl_2002, Kim_2012, Juwle_2012, Solano_2013, Stavropoulo_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014). All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000239343	SCV001251952	pathogenic	Familial cancer of breast	2020-05-03	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000019240	SCV001434965	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-08	criteria provided, single submitter	clinical testing	This c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is predicted to introduce a premature translational termination codon. This variant is extremely rare in the general population according to the gnomAD database. It has been reported in multiple unrelated patients with breast cancer or ovary cancer [2PMID: 7894493, 21324516, 22006311, 22752604, 24218521, 24010542].Therefore, the c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159978	SCV001449657	pathogenic	not provided	2016-12-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159978	SCV002017917	pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing
DASA	RCV000019240	SCV002498794	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-10	criteria provided, single submitter	clinical testing	The c.3607C>T;p.(Arg1203*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17671; PMID: 21324516; PMID: 22006311; PMID: 24010542; PMID: 22752604) - PS4. The variant is present at low allele frequencies population databases (rs62625308 – gnomAD 0.0001195%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 7894493) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159978	SCV002550996	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019240	SCV002576482	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-13	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
MGZ Medical Genetics Center	RCV000019240	SCV002579635	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-01-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000019240	SCV004046890	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1203*) 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 present in population databases (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671) classified as pathogenic . For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000239343	SCV004100708	pathogenic	Familial cancer of breast	2024-06-10	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
PreventionGenetics, part of Exact Sciences	RCV004554605	SCV004111617	pathogenic	BRCA1-related disorder	2023-05-16	criteria provided, single submitter	clinical testing	The BRCA1 c.3607C>T variant is predicted to result in premature protein termination (p.Arg1203*). This variant has been widely reported in individuals with hereditary breast and ovarian cancer (see for example, Table 2a, Friedman et al. 1994. PubMed ID: 7894493; Table 1, Meindl et al. 2002. PubMed ID: 11802209). This variant was also reported as germline variant in a patient with renal cell carcinoma (Table S3, Santos et al. 2021. PubMed ID: 33442023). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243941-G-A), and it is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17671/). Taken together, this variant is interpreted as pathogenic.
Baylor Genetics	RCV000019240	SCV004215080	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802939	SCV004817779	pathogenic	BRCA1-related cancer predisposition	2024-07-29	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 observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 chromosomes 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000019240	SCV005045930	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000159978	SCV005199728	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004808551	SCV005431506	pathogenic	Inherited breast cancer and ovarian cancer	2024-09-06	criteria provided, single submitter	clinical testing	PVS1,PM5_Strong
Fulgent Genetics, Fulgent Genetics	RCV005016279	SCV005647150	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000019240	SCV000039528	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019240	SCV000053711	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-10-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019240	SCV000144807	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148389	SCV000190087	pathogenic	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048251	SCV000587321	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000159978	SCV000591455	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Arg1203X variant has been previously reported in the literature in 7 of 12470 individuals with hereditary breast or ovarian cancer (Selected publications: Konstantopoulou 2008, Manguoglu 2003, Borg 2010, Kim 2012). The variant was also reported 22 times in the UMD database ase "causal" and 31 times in the BIC database as "clinically important". The variant was also reported 1 time in the ESP project at low frequency (0.0002) and by dbSNP (ID: rs62625308). This variant leads to a premature stop codon at position 1203, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000019240	SCV000733624	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735444	SCV000863580	pathogenic	Breast and/or ovarian cancer	2013-12-20	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785373	SCV000923944	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001642230	SCV001852763	pathogenic	Ovarian carcinoma	2021-09-11	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159978	SCV001958763	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000159978	SCV002035659	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000239343	SCV002520875	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162256	SCV002758504	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332084	SCV004040476	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
BRCAlab, Lund University	RCV000019240	SCV004244035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing