rs397509067
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3436_3439delTGTT(p.Cys1146LeufsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C1146C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 frameshift
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3436_3439delTGTT | p.Cys1146LeufsTer8 | frameshift_variant | Exon 10 of 23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3436_3439delTGTT | p.Cys1146LeufsTer8 | frameshift_variant | Exon 10 of 23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6
Variant allele predicted to encode a truncated non-functional protein.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Cys1146Leufs*8) 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 and/or ovarian cancer (PMID: 10644434, 22798144, 22923021, 25452441). This variant is also known as 3555del4. ClinVar contains an entry for this variant (Variation ID: 54885). For these reasons, this variant has been classified as Pathogenic.
Variant summary: BRCA1 c.3436_3439delTGTT (p.Cys1146LeufsX8) 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 251228 control chromosomes. c.3436_3439delTGTT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Wagner_1999, Couch_2015, Kim_2012, Moradian_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast or ovarian cancer (PMID: 22798144, 22923021, 25452441, 29093764, 30630526, 33558524, 35281878). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
The c.3436_3439delTGTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3436 to 3439, causing a translational frameshift with a predicted alternate stop codon (p.C1146Lfs*8). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families (Wagner T et al. Genomics 1999 Dec; 62(3):369-76; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Novakovi S et al. Int. J. Oncol. 2012 Nov; 41(5):1619-27; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Jian W et al. Hered Cancer Clin Pract, 2017 Oct;15:19; Apessos A et al. Cancer Genet, 2018 01;220:1-12; Yi D et al. Hum. Genomics, 2019 01;13:4; Farra C et al. Hered Cancer Clin Pract, 2019 Jan;17:4). Of note, this alteration may also be designated as 3555delTGTT, 3553delTTTG or 3555_3558delTGTT. 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.
Familial cancer of breast Pathogenic:2
ACMG Guidelines 2015 criteria The BRCA1 p.Cys1146Leufs variant is a known pathogenic variant in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 27 pathogenic variants (PM1 Pathogenic Moderate). The deletion causes a frameshift, which changes a Cysteine to a Leucine at codon 1146, and introduces a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299942.2) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study the variant Cys1146Leufs was found twice in a 32 and a 45- year-old female with unilateral breast cancer and family history of breast cancer, respectively. Therefore, this variant was classified as a Pathogenic.
not specified Pathogenic:1
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S Pathogenic:1
not provided Pathogenic:1
This deletion of four nucleotides in BRCA1 is denoted c.3436_3439delTGTT at the cDNA level and p.Cys1146LeufsX8 at the protein level. This variant, also known as BRCA1 3555del4 using alternate nomenclature, has been reported as a pathogenic variant (Wagner 1999, Audeh 2010, Novakovic 2012). The normal sequence with the bases that are deleted in brackets is GGTT[TGTT]CTGA. The deletion cases a frameshift,which changes a Cysteine to a Leucine at codon 1146, and introduces a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.
Malignant tumor of breast Pathogenic:1
The p.Cys1146LeufsX8 variant has been previously reported in the literature in one study (Wagner 1999). This deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1146 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the BRCA1 gene is an established disease mechanism for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at