rs80359876
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.4964_4982delCTGGCCTGACCCCAGAAGA(p.Ser1655TyrfsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S1655S) has been classified as Uncertain significance. 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 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.4964_4982delCTGGCCTGACCCCAGAAGA | p.Ser1655TyrfsTer16 | frameshift_variant | Exon 15 of 23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.4964_4982delCTGGCCTGACCCCAGAAGA | p.Ser1655TyrfsTer16 | frameshift_variant | Exon 15 of 23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00 AC: 0AN: 250074 AF XY: 0.00
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461814Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727230 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9
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.
Variant allele predicted to encode a truncated non-functional protein.
ACMG Criteria: PVS1, PS4, PM2, PP5_M; Variant was found in heterozygous state in Proband.
The c.4964_4982del (p.Ser1655Tyrfs*16) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 9145677, 11462242 referred as 5083del19 in some publications]. This variant is considered a founder mutation in Southern Italy [PMID 11462242]. This 19 bp deletion in exon 15 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been detected in the ExAC database . This variant thus classified as pathogenic.
The c.4964_4982del;p.(Ser1655Tyrfs*16) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18980973) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 37616; PMID: 29446198; PMID: 27067391; PMID: 26681312; PMID: 26219728; PMID: 22711857; PMID: 21702907; PMID: 23199084)PS4. This variant is not present in population databases (rs80359876- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Hereditary breast ovarian cancer syndrome Pathogenic:6Other:1
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 9/19/2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Variant summary: BRCA1 c.4964_4982del19 (p.Ser1655TyrfsX16) 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 250074 control chromosomes. c.4964_4982del19 has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Thirteen clinical diagnostic laboratories, one expert panel (ENIGMA) and one consortium (CIMBA) 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.
This sequence change creates a premature translational stop signal (p.Ser1655Tyrfs*16) 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 ovarian cancer (PMID: 9145677, 11462242, 11938448, 16847550, 17221156, 18159056, 23199084, 26219728, 26681312). This variant is also known as 5083del19. ClinVar contains an entry for this variant (Variation ID: 37616). For these reasons, this variant has been classified as Pathogenic.
not provided Pathogenic:6
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; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5083del19; This variant is associated with the following publications: (PMID: 27741520, 9145677, 16847550, 11056688, 25415331, 23199084, 26219728, 21324516, 18159056, 11462242, 11938448, 17221156, 15340362, 22711857, 18980973, 24618965, 20608970, 26295337, 27067391, 27463008, 26976419, 26852130, 26681312, 28161869, 30736435, 31447099, 32854451)
PP5, PM2, PS4_moderate, PVS1
The BRCA1 c.4964_4982del; p.Ser1655TyrfsTer16 variant (rs80359876), also known as 5083del19, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer (Couch 1997, Finch 2016, Giannini 2006, John 2007), and is considered a founder mutation in Italy (Baudi 2001, Mucaki 2016, Nedelcu 2002, Russo 2007, Russo 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37616), and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 19 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional analyses of the variant protein show a truncated protein product and major changes to the transcriptional profile of cells with the variant (Quaresima 2008). Based on available information, the p.Ser1655TyrfsTer16 variant is considered to be pathogenic. References: Baudi F et al. Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer. Hum Mutat. 2001 Aug;18(2):163-4. PMID: 11462242. Couch FJ et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409-15. PMID: 9145677. Finch A et al. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2016 Mar;89(3):304-11. PMID: 26219728. Giannini G et al. Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families. Breast Cancer Res Treat. 2006 Nov;100(1):83-91. PMID: 16847550. John EM et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007 Dec 26;298(24):2869-76. PMID: 18159056. Mucaki EJ et al. A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genomics. 2016 Apr 11;9:19. PMID: 27067391. Nedelcu R et al. BRCA mutations in Italian breast/ovarian cancer families. Eur J Hum Genet. 2002 Feb;10(2):150-2. PMID: 11938448. Russo A et al. BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat. 2007 Nov;105(3):267-76. PMID: 17221156. Russo A et al. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat. 2009 Jan;113(1):67-70. PMID: 18228134. Quaresima B et al. BRCA1 5083del19 mutant allele selectively up-regulates periostin expression in vitro and in vivo. Clin Cancer Res. 2008 Nov 1;14(21):6797-803. PMID: 18980973.
The BRCA1 c.4964_4982del (p.Ser1655Tyrfs*16) variant (also known as 5083del19) alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast/ovarian cancer and as a founder mutation in southern Italy (PMIDs: 32854451 (2020), 26219728 (2016), 26681312 (2015), 22711857 (2012), 11462242 (2001), 9145677 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 19 nucleotides in exon 15 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 at least ten individuals affected with breast and/or ovarian cancer (PMID: 11462242, 16847550, 17221156, 18159056, 22711857, 26681312, 32854451) and in several dozens of suspected hereditary breast and ovarian cancer families (PMID: 9145677, 11938448, 26219728, 29446198, 30736435, 36329109). A haplotype analysis has indicated that this is a recurrent mutation and a possible founder mutation in Italy (PMID: 18228134). 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.4964_4982del19 pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of 19 nucleotides between nucleotide positions 4964 and 4982, causing a translational frameshift with a predicted alternate stop codon (p.S1655Yfs*16). This alteration has been reported in multiple families with hereditary breast and ovarian cancer (HBOC) syndrome and has also been established as a founder mutation of Southern Italian origin (Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Baudi F et al. Hum. Mutat. 2001 Aug;18:163-4; Janaviius R. EPMA J. 2010 Sep;1:397-412; Russo A et al. Breast Cancer Res. Treat. 2009 Jan;113:67-70; Finch A et al. Clin. Genet. 2016 Mar;89:304-11). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). Of note, this alteration is also designated as 5083del19 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Breast and/or ovarian cancer Pathogenic:1
BRCA1-related cancer predisposition Pathogenic:1
This variant deletes 19 nucleotides in exon 15 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 at least ten individuals affected with breast and/or ovarian cancer (PMID: 11462242, 16847550, 17221156, 18159056, 22711857, 26681312, 32854451) and in several dozens of suspected hereditary breast and ovarian cancer families (PMID: 9145677, 11938448, 26219728, 29446198, 30736435, 36329109). A haplotype analysis has indicated that this is a recurrent mutation and a possible founder mutation in Italy (PMID: 18228134). 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.
Malignant tumor of breast Pathogenic:1
The p.Ser1655TyrfsX16 variant has been identified in 5 of 574 proband chromosomes (frequency 0.009) in individuals with breast and ovarian cancer (Couch 1997, Baudi 2001). In addition, this variant is identified in the BIC database 46 times and indicated as a clinically important variant and in the UMD database 7 times as "causal". The p.Ser1655Tyrfsx16 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1655 and leads to a premature stop codon 16 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer syndromes. In summary, based on the information above, this variant is classified as pathogenic.
Familial cancer of breast Pathogenic:1
Ovarian neoplasm Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at