Submissions for variant NM_007294.4(BRCA1):c.3598C>T (p.Gln1200Ter)

dbSNP: rs62625307

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077552	SCV000282310	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	RCV000048245	SCV000076258	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1200*) 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 (rs62625307, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 9452076, 22006311, 22711857, 24333842, 25682074). This variant is also known as 3717C>T. ClinVar contains an entry for this variant (Variation ID: 54929). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131819	SCV000186874	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The p.Q1200* pathogenic mutation (also known as c.3598C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3598. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been identified in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Tartaglini E et al. Hum. Mutat. 1998;Suppl 1:S163-6; Liede A et al. Am J Hum Genet, 2002 Sep;71:595-606; Latimer JJ et al. BMC Med. Genet. 2005 Jun;6:26; John EM et al. JAMA, 2007 Dec;298:2869-76; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Torres-Mejía G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Villarreal-Garza C et al. Breast Cancer Res Treat, 2015 Apr;150:389-94; Rashid MU et al. BMC Cancer. 2016 08;16:673; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). Of note, this alteration is also designated as 3717C>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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077552	SCV000195922	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000159977	SCV000210149	pathogenic	not provided	2023-06-30	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; 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 3717C>T; This variant is associated with the following publications: (PMID: 27221827, 16162645, 29161300, 18159056, 16267036, 32211327, 29922827, 28888541, 24333842, 25525159, 9452076, 22006311, 25682074, 25716084, 25371446, 25085752, 22711857, 27425403, 27553291, 28127413, 29061967, 28985766, 15955237, 29446198, 29907814, 30706980, 30720243, 31528241, 31454914, 31825140, 31742824, 33758026, 35264596, 35875314, 36385461, 35377489)
Color Diagnostics, LLC DBA Color Health	RCV000131819	SCV000292158	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-21	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 at least 10 individuals affected with breast and ovarian cancer (PMID: 9452076, 12181777, 15955237, 16162645, 18159056, 22006311, 22711857, 25371446, 25682074, 27553291, 33606809). This variant has been identified in 1/250916 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159977	SCV000296303	pathogenic	not provided	2024-10-25	criteria provided, single submitter	clinical testing	The BRCA1 c.3598C>T (p.Gln1200*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35377489 (2022), 33758026 (2022), 33606809 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/), 31742824 (2020), 31528241 (2019), 31454914 (2019), 29161300 (2017), 28888541 (2017), 27553291 (2016), 25371446 (2014), 22006311 (2011), 18159056 (2007), 16162645 (2006), 15955237 (2005)). The frequency of this variant in the general population, 0.000004 (1/250916 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077552	SCV000325695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077552	SCV000488352	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048245	SCV000699043	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3598C>T (p.Gln1200X) 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 4e-06 in 250916 control chromosomes (gnomAD). c.3598C>T has been reported in the literature in multiple individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Tartaglini_1998, Liede_2002, Judkins_2005, Latimer_2005, Beetstra_2006, John_2007, Torres-Mejia_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Eleven ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000048245	SCV000839252	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763003	SCV000893448	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001611	SCV001159056	pathogenic	not specified	2018-07-02	criteria provided, single submitter	clinical testing	The BRCA1 c.3598C>T; p.Gln1200Ter variant (rs62625307), also known as 3717C>T, has been described in the literature in individuals with hereditary breast and ovarian cancer (Alemar 2016, Rashid 2016, Tartaglini 1998, Walsh 2011). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 54929) and is only observed on 1 allele in the Genome Aggregation Database. This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. Rashid M et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Tartaglini E et al. Three novel germline BRCA1 mutations in early-onset breast and ovarian cancer families. Hum Mutat. 1998;Suppl 1:S163-6. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032-7.
Revvity Omics, Revvity	RCV000159977	SCV003809779	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077552	SCV004212721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077552	SCV004817782	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-04	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 over ten individuals and families affected with breast and ovarian cancer (PMID: 9452076, 12181777, 15955237, 16162645, 18159056, 22006311, 22711857, 25371446, 25682074, 27425403, 27553291). This variant has been identified in 1/250916 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.
CeGaT Center for Human Genetics Tuebingen	RCV000159977	SCV005092460	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Sharing Clinical Reports Project (SCRP)	RCV000077552	SCV000109353	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-01-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077552	SCV000144801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048245	SCV000587320	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048245	SCV001950158	pathogenic	Hereditary breast ovarian cancer syndrome	2021-09-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554663	SCV004119878	pathogenic	BRCA1-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The BRCA1 c.3598C>T variant is predicted to result in premature protein termination (p.Gln1200*). This variant has been reported to be causative for breast and ovarian cancer (Walsh et al. 2011. PubMed ID: 22006311; Alsop et al. 2012. PubMed ID: 22711857, Supplementary Table 2; Wong-Brown et al. 2015. PubMed ID: 25682074). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/54929/evidence/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
BRCAlab, Lund University	RCV000077552	SCV004244039	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing