rs80357696

Positions:

• chr17-43124016-CCAGATGGGACA-C

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.70_80del​(p.Cys24SerfsTer13) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,609,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 4.47

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1690 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43124016-CCAGATGGGACA-C is Pathogenic according to our data. Variant chr17-43124016-CCAGATGGGACA-C is described in ClinVar as [Pathogenic]. Clinvar id is 55676.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43124016-CCAGATGGGACA-C is described in Lovd as [Pathogenic]. Variant chr17-43124016-CCAGATGGGACA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.70_80del	p.Cys24SerfsTer13	frameshift_variant, splice_region_variant	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.70_80del	p.Cys24SerfsTer13	frameshift_variant, splice_region_variant	2/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456976 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725172

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
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	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 27, 2023	This variant deletes the last 11 nucleotides in exon 2 in 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 is also known as 188del11 and 189del11 in the literature. This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7837387, 8651293, 10498392, 18779604, 22711857, 25682074, 26543556) and one individual each affected with endometrial (PMID: 8651293) and pancreatic cancer (PMID: 28767289). This variant has been identified in 21 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	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 in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 189_199del11 or c.69_79delGTGTCCCATCT; This variant is associated with the following publications: (PMID: 16267036, 7837387, 7545954, 18779604, 26543556, 8651293, 12402332, 10498392, 8533757, 28767289, 31090900, 30787465, 31464824, 25682074, 36098958, 34022715, 34887416) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2022	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast cancer, PMIDs: 22711857 (2012), 26543556 (2015), and 25682074 (2015)) and pancreatic cancer (PMID: 28767289 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2022	DNA sequence analysis of the BRCA1 gene demonstrated a 11 base pair deletion in exon 2, c.70_80del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 12 amino acids downstream of the change, p.Cys24Serfs*13. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. The c.70_80del sequence change has not been described in the population databases such as ExAC and gnomAD (dbSNP rs1220450191). This pathogenic sequence change has previously been described in an individual with breast cancer and ovarian cancer (PMID: 7837387, 10498392, 25682074, 22711857, 26543556). -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change creates a premature translational stop signal (p.Cys24Serfs*13) 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 cancer and ovarian cancer (PMID: 2246425, 7837387, 10498392, 20104584, 22711857, 25682074, 26543556). This variant is also known as 188del11 and 189del11. ClinVar contains an entry for this variant (Variation ID: 55676). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2022	Variant summary: BRCA1 c.70_80del11 (p.Cys24SerfsX13) 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 251038 control chromosomes.The variant, c.70_80del11, has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (eg. Berman_1996, Hopper_1999, Alsop_2012, Dean_2015, Wong-Brown_2015). 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. Nine ClinVar submissions including 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	Color Diagnostics, LLC DBA Color Health	Apr 19, 2022	This variant deletes the last 11 nucleotides in exon 2 in 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 is also known as 188del11 and 189del11 in the literature. This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer (PMID: 7837387, 8651293, 10498392, 18779604, 22711857, 25682074, 26543556) and one individual each affected with endometrial (PMID: 8651293) and pancreatic cancer (PMID: 28767289). This variant has been identified in 21 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2019	The c.70_80del11 pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a deletion of 11 nucleotides at nucleotide positions 70 to 80, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*13). This mutation has been reported in multiple individuals with hereditary breast, ovarian, and/or pancreatic cancer (Berman DB et al. Am. J. Hum. Genet. 1996 Jun;58:1166-76; Frank TS et al. J. Clin. Oncol. 2002 Mar;20:1480-90; Kurian A et al. J. Clin. Oncol. 2008 Oct;26(29):4752-8; Shindo K et al. J. Clin. Oncol. 2017 Oct;35(30):3382-3390). Of note, this alteration is also designated as 188del11 and 189del11 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. -

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: rs80357696; hg19: chr17-41276033;