rs80359876

chr17-43070931-TTCTTCTGGGGTCAGGCCAG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):c.4964_4982del(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. 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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27 O:1
• Conservation: PhyloP100: 4.31

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43070931-TTCTTCTGGGGTCAGGCCAG-T is Pathogenic according to our data. Variant chr17-43070931-TTCTTCTGGGGTCAGGCCAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37616.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43070931-TTCTTCTGGGGTCAGGCCAG-T is described in Lovd as [Pathogenic]. Variant chr17-43070931-TTCTTCTGGGGTCAGGCCAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4964_4982del	p.Ser1655TyrfsTer16	frameshift_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4964_4982del	p.Ser1655TyrfsTer16	frameshift_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9

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	Counsyl	Feb 19, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 16, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	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. -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 06, 2024	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) and in several dozens of suspected hereditary breast and ovarian cancer families (PMID: 9145677, 11938448, 26219728, 29446198). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	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. -
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	Mar 01, 2021	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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 08, 2022	PP5, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 07, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 12, 2019	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; Janavičius 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. 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	Feb 28, 2023	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) and in several dozens of suspected hereditary breast and ovarian cancer families (PMID: 9145677, 11938448, 26219728, 29446198). 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 31, 2018

The BRCA1 c.4964_4982del19; p.Ser1655fs 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 general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), 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 c.4964_4982del19 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. 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. Finch A et al. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2016 Mar;89(3):304-11. 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. John EM et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007 Dec 26;298(24):2869-76. 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. Nedelcu R et al. BRCA mutations in Italian breast/ovarian cancer families. Eur J Hum Genet. 2002 Feb;10(2):150-2. 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. 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. 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Nov 26, 2012

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359876; hg19: chr17-41222948;