rs80357970

Positions:

• chr17-43093055-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.2475del​(p.Asp825GlufsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,794 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. D825D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 0.394

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43093055-TG-T is Pathogenic according to our data. Variant chr17-43093055-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37472.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093055-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43093055-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2475del	p.Asp825GlufsTer21	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2475del	p.Asp825GlufsTer21	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250912 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461578 Hom.: 0 Cov.: 41 AF XY: 0.0000165 AC XY: 12 AN XY: 727106

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 10, 2024	- -
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, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Mar 07, 2020	This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result in an unstable transcript that is degraded by nonsense-mediated decay, a well-established mechanism of disease for the BRCA1 gene (Borg 2010). In the literature, this variant has been observed in individuals with breast cancer, ovarian cancer, and prostate cancer and has been noted to occur more commonly in individuals of Scandinavian descent (Cunningham (2014), Janavicius (2010), Larsen (2013), Leongamornlert (2012), Schneegans (2012), Thomassen (2008)). Based on this information, we consider this variant to be pathogenic. PS4; PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 30, 2019	This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 8595428, 18465347). Therefore, the c.2475delC (p.Asp825Glufs*21) variant in the BRCA1 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 01, 2015	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	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, and considered a common founder variant in the Scandinavian population (Plummer 1995, Janaviius 2010, Leongamornlert 2012, Schneegans 2012, Pennington 2013, Cunningham 2014, Maxwell 2017); 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 2594delC; This variant is associated with the following publications: (PMID: 22811390, 22516946, 17694537, 8595428, 23747895, 26833046, 28476184, 29625052, 26689913, 24504028, 22160602, 23199084, 24728189, 23704984, 17688236, 25452441, 18465347, 20104584, 28049106, 28087643, 27798111, 27375368, 28776284, 28831036, 29339979, 29433453, 30720243, 30322717, 32050665, 31263571, 31883735, 11391658, 34399810, 32719484, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2024	PM5_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 21, 2023	This variant 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 and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 31263571 (2019), 24504028 (2014), 22811390 (2013), 20104584 (2010), 18465347 (2008), 8595428 (1995)), pancreatic cancer (PMID: 29433453 (2018)), renal cancer (PMID: 32782288 (2020)), and prostate cancer (PMID: 22516946 (2012)). 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	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
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	Jun 08, 2016	Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.2515delC, c.2679_2682delGAAA, c.2681_2682delAA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121366 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature, and has been described as a common mutation in individuals of Scandinavian ancestry. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 12/24/2018 by Invitae and 11/29/2016 by GeneDx. 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Asp825Glufs*21) 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 (rs80357970, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 8595428, 18465347, 20104584, 22160602, 22516946, 23199084, 23704984, 24307375, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as 2594delC. ClinVar contains an entry for this variant (Variation ID: 37472). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Asp825GlufsX21 variant in BRCA1 has been reported in >25 individuals with BRCA1-related cancers and has been reported as a founder variant in Scandinavian populations (Pennington 2013, Cunningham 2014, Maxwell 2017, Hakansson 1997, BIC database). It has also been identified in 1/113380 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 825 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37472). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2021	The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing a translational frameshift with a predicted alternate stop codon (p.D825Efs*21). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date and has been described as a Scandinavian/Northern European founder mutation (Plummer SJ et al. Hum. Mol. Genet. 1995 Oct;4:1989-91; Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Lancaster JM et al. Br. J. Cancer. 1998 Dec;78:1417-20; Johannsson O et al. Eur. J. Cancer. 1999 Aug;35:1248-57; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Thomassen M et al. Acta Oncol. 2008;47:772-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Janaviius R. EPMA J. 2010 Sep;1:397-412; Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Schneegans SM et al. Fam. Cancer, 2012 Jun;11:181-8; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Maxwell KN et al. Nat Commun, 2017 08;8:319; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in familial prostate cancer cohorts (Leongamornlert D et al. Br. J. Cancer. 2012 May;106:1697-701; Li D et al. Front Biosci (Landmark Ed). 2013 Jun;18:1445-59), as well as a uterine serous carcinoma cohort (Pennington KP et al. Cancer, 2013 Jan;119:332-8). It was also seen in a male patient with pancreatic cancer (Ibrahim M et al. BMC Cancer. 2018 02;18(1):179). Of note, this alteration is also designated as 2594delC and rs80357970 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	Aug 31, 2022	This variant deletes 1 nucleotide 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 detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 25, 2019

The BRCA1 c.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome (Cunningham 2014, Pennington 2013, Schneegans 2012). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 37472). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Pennington K et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013; 119(2):332-8. Schneegans S et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012; 11(2):181-8. -

BRCA1-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 25, 2024

This variant deletes 1 nucleotide 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 detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 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. -

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

Feb 12, 2022

- -

BRCA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian cancer (Maxwell et al. 2017. PubMed ID: 28831036; Cunningham et al. 2014. PubMed ID: 24504028), pancreatic cancer (Ibrahim et al. 2018. PubMed ID: 29433453), and prostate cancer (Leongamornlert et al. 2012. PubMed ID: 22516946). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37472/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357970; hg19: chr17-41245072;