rs80357727
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4041_4042del(p.Gly1348AsnfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R1347R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 frameshift
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.4041_4042del | p.Gly1348AsnfsTer7 | frameshift_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4041_4042del | p.Gly1348AsnfsTer7 | frameshift_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
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 | Institute of Human Genetics, University of Leipzig Medical Center | Mar 03, 2023 | Criteria applied: PVS1, PS4, PM2_SUP - |
Pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_007294.4:c.4041_4042del (chr17:430914889) in BRCA1 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 30, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | Frameshift 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 or family history consistent with pathogenic variants in this gene (Eccles et al., 1998; Kang et al., 2002; Laitman et al., 2011; Kim et al., 2012; Kwon et al., 2018; Mehta et al., 2018; Ryu et al., 2019); 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 (gnomAD); Also known as 4160_4161del; This variant is associated with the following publications: (PMID: 23697973, 9649133, 25330149, 26843898, 22864640, 30555256, 28111427, 27488874, 30350268, 17921118, 19016756, 22006311, 12204006, 25483746, 22798144, 27083178, 26187060, 20960228, 26845104, 28152038, 28724667, 30352249, 30309222, 30702160, 33726785, 31825140, 32101877, 34645131, 28888541) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 17, 2020 | The BRCA1 c.4041_4042del (p.Gly1348Asnfs*7) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals affected with breast cancer and/or ovarian cancer (PMID: 9649133 (1998), 27488874 (2017), 25330149 (2015), 23697973 (2012)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This is a deletion of 2 base pairs, which results in frameshift and creation of a stop codon 7 amino acid residues later. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the literature as 4160delAG. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 23, 2021 | PVS1, PM2, PS4 - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change creates a premature translational stop signal (p.Gly1348Asnfs*7) 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 hereditary breast and/or ovarian cancer (PMID: 9649133, 12204006, 23697973, 25330149, 25418591, 27083178). ClinVar contains an entry for this variant (Variation ID: 55082). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2022 | Variant summary: BRCA1 c.4041_4042delAG (p.Gly1348AsnfsX7) 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 251088 control chromosomes. c.4041_4042delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Walsh_2011, Troudi_2007, Sugano_2008, Kim_2012, Eccles_1998, Judkins_2005). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2022 | The c.4041_4042delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4041 to 4042, causing a translational frameshift with a predicted alternate stop codon (p.G1348Nfs*7). This mutation has been reported in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Eccles DM et al. Br. J. Cancer. 1998 Jun;77:2199-203; Troudi W et al. J Hum Genet, 2007 Oct;52:915-920; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Fourati A et al. Bull Cancer. 2014 Nov;101:E36-40; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Riahi A et al. Breast Cancer, 2017 Mar;24:238-244; Eoh KJ et al. Cancer Res Treat. 2017 Apr;49(2):408-415; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Mehta A et al. Cancer Manag Res, 2018 Nov;10:6505-6516; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Wu H et al. Hum Hered, 2019 Feb;84:160-169). Of note, this alteration is also designated as c.4041delAG, 4158delAG and 4160delAG 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2023 | This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4158delAG, 4159delGA and 4160delAG according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over ten unrelated individuals affected with breast or ovarian cancer (PMID: 9649133, 12204006, 19016756, 22006311, 23697973, 25330149, 25418591, 27083178, 27488874, 29673794, 30555256, 32101877; Color internal data). 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 the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 15, 2021 | - - |
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 | Nov 24, 2021 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at