rs80357888

chr17-43094022-CTTTAA-C

Variant summary

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

The NM_007294.4(BRCA1):c.1504_1508del(p.Leu502AlafsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,764 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. L502L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28 O:1
• Conservation: PhyloP100: 3.18

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 17-43094022-CTTTAA-C is Pathogenic according to our data. Variant chr17-43094022-CTTTAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37417.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094022-CTTTAA-C is described in Lovd as [Pathogenic]. Variant chr17-43094022-CTTTAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1504_1508del	p.Leu502AlafsTer2	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1504_1508del	p.Leu502AlafsTer2	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251068 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135696

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: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461764 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727166

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant deletes 5 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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least 15 individuals affected with breast and ovarian cancer (PMID: 11376024, 19491284, 20104584, 21204799, 23479189, 23536787, 24010542, 24372583, 24728189, 26296701, 28993434, 30078507, 30130155, 33471991; Leiden Open Variation Database DB-ID BRCA1_001306; Color internal data). This variant has been identified in 3/251068 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. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
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	Genetics and Molecular Pathology, SA Pathology	Aug 17, 2020	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	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 BRCA1-related cancers (Peelen 1997, Ellingson 2015, Laraqui 2015, Riahi 2015); 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 1623del5 and 1623_1627delTTAAA; This variant is associated with the following publications: (PMID: 9150151, 26187060, 17262179, 27836010, 25814778, 10737987, 11857748, 23479189, 24372583, 26296701, 27211102, 28127413, 27025497, 26577449, 28152038, 27062684, 29907814, 28993434, 31159747, 30322717, 30720243, 30078507, 30720863, 30702160, 29176636) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2021	This frameshift variant causes the premature termination of BRCA1 protein synthesis. It has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 9150151 (1997), 24312913 (2013), 23479189 (2013), 27836010 (2016), 28993434 (2018), 23536787 (2013), 24372583 (2015), 30078507 (2018), 30322717 (2018), 30702160 (2019), 30720863 (2019), and 31159747 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	BRCA1: PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Leu502Alafs*2) 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 (rs80357888, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 20104584, 23479189, 23536787, 24372583, 26296701). This variant is also known as 1623del5. ClinVar contains an entry for this variant (Variation ID: 37417). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2021	Variant summary: BRCA1 c.1504_1508delTTAAA (p.Leu502AlafsX2) 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 allele was found at a frequency of 1.2e-05 in 251068 control chromosomes. c.1504_1508delTTAAA 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen clinical diagnostic laboratories, one consortium (CIMBA), and one 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

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	The c.1504_1508delTTAAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 1504 to 1508, causing a translational frameshift with a predicted alternate stop codon (p.L502Afs*2). This mutation has been detected in multiple breast and/or ovarian cancer families of various ethnicities to date (Peelen T et al. Am. J. Hum. Genet. 1997 May;60(5):1041-9; Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9; Stavropoulou AV et al. PLoS One. 2013 Mar;8(3):e58182; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12(4):767-77; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Riahi A et al. Clin. Genet. 2015 Feb;87(2):155-60; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103)(Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Of note, this alteration is also designated as 1623del5 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	Oct 19, 2023	This variant deletes 5 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 detected in at least 15 individuals affected with breast and ovarian cancer (PMID: 11376024, 19491284, 20104584, 21204799, 23479189, 23536787, 24010542, 24372583, 24728189, 26296701, 28993434, 30078507, 30130155, 33471991; Leiden Open Variation Database DB-ID BRCA1_001306; Color internal data). This variant has been identified in 3/251068 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. -

bilateral breast cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria The BRCA1 p.Leu502Alafs is a known pathogenic frameshift variant in exon 11 and in the serine-rich domain (A344-507R aa) with limited information, however there's information about the SQ (serine-glutamine rich) cluster, whose phosphorylation is critical for allowing adequate time for completing normal Homologous Recombination Repair (HRR) prior to mitosis and preventing cells from entering G1 prematurely resulting in gross chromosomal aberrations (PMID: 28039444). The deletion causes a frameshift, which changes a Leucine to an Alanine at codon 502, and creates a premature stop codon at position 2 of the new reading frame, and this null variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is also in a mutational hotspot of 32 pathogenic frameshift and nonsense variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.0000119 which is less than the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282260.1) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was seen in a 40 years old female with bilateral breast cancer and no reported family history of cancer. Therefore, this variant was classified as a Pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Leu502AlafsX2 variant was identified in 11 of 12654 proband chromosomes (frequency: 0.0009) from individuals or families with breast and ovarian cancer (Borg 2010, de Juan Jimenez 2013, Ellingson 2015, Konstantopoulou 2000, Peelen 1997, Riahi 2015, Stavropoulou 2013, Van Der Merwe 2012, Wong-Brown 2015); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the following databases: dbSNP (ID: rs80357888) as "With Pathogenic allele", ClinVar (13x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in tumour of the ovary), LOVD 3.0 (15x), UMD-LSDB (13x causal), BIC Database (29x pathogenic), and ARUP Laboratories (definitely pathogenic). The variant was not identified in the MutDB or the Zhejiang Colon Cancer Databases. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1504_1508delTTAAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 502 and leads to a premature stop codon at position 503. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jan 01, 2020

This sequence change deletes 5 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 502 and the creation of a premature translation stop signal 2 amino acid residues later- p.(Leu502Alafs). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This sequence change has been described in individuals and families affected with breast and/or ovarian cancer (PMID: 23479189, 20104584, 24372583 26296701). This mutation has been described in the mutation database ClinVar (Variation ID: 37417) -

Dysgerminoma Other:1

other, no assertion criteria provided

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 01, 2016

- 3: Mutations in other consensus cancer genes, not currently considered targetable

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: rs80357888; hg19: chr17-41246039;