rs62625307
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3598C>T(p.Gln1200Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1200Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.3598C>T | p.Gln1200Ter | stop_gained | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.3598C>T | p.Gln1200Ter | stop_gained | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250916Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135662
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727168
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 13, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 26, 2012 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 30, 1999 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 04, 2024 | 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. - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2021 | 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. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | 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. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 04, 2019 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in individuals affected with breast or fallopian tube cancer in the published literature (PMID: 27553291 (2016), 25371446 (2014), 22006311 (2011), 18159056 (2007)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BRCA1: PVS1, PM2, PS4:Moderate - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 21, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2022 | 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. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 02, 2018 | 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. - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
BRCA1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 01, 2022 | 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 (http://gnomad.broadinstitute.org/variant/17-41243950-G-A). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at