rs80357780

Positions:

• chr17-43093233-ACT-A

Variant summary

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

The ENST00000357654.9(BRCA1):​c.2296_2297del​(p.Ser766Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,756 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. S766S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 1.66

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 17-43093233-ACT-A is Pathogenic according to our data. Variant chr17-43093233-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 17666.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093233-ACT-A is described in Lovd as [Pathogenic]. Variant chr17-43093233-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2296_2297del	p.Ser766Ter	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.2296_2297del	p.Ser766Ter	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251084 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This variant deletes 2 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 reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 7894493, 8533757, 16030099, 18821011, 22798144, 25863477, 26028024, 32438681, 34072659). This variant has been identified in 12 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). In a large breast cancer case-control study (PMID: 33471991), this variant has been observed in 2/60466 cases and 1/53461 unaffected controls. This variant has been identified in 1/251084 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	literature only	OMIM	Dec 01, 1994	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 23, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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	Aug 09, 2023	This sequence change creates a premature translational stop signal (p.Ser766*) 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 (rs80357780, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 7894493, 18821011, 22798144, 25863477, 26028024). In at least one individual the variant was observed to be de novo. This variant is also known as 2415delAG. ClinVar contains an entry for this variant (Variation ID: 17666). 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	Sep 29, 2023	Variant summary: BRCA1 c.2296_2297delAG (p.Ser766X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251084 control chromosomes (gnomAD). c.2296_2297delAG 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. The following publication has been ascertained in the context of this evaluation (PMID: 29446198). Eight submitters (including ENIGMA expert panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Ser766X variant in BRCA1 has been reported in 18 individuals with BRCA1-related cancers (Friedman 1994 PMID: 7894493; Weitzel 2005 PMID: 16030099; Azzollini 2016 PMID: 27062684; Rebbeck 2018 PMID: 29446198; Singh 2018 PMID: 29470806; Fernandez-Lopez 2019 PMID: 30630528). It has also been identified in 0.003% (1/34580) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17666). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 766 and leads directly to a premature termination codon. 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 (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Nonsense 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 (Papi 2009, Kim 2012, Weitzel 2005, Azzollini 2016, Singh 2018); Not observed at a significant frequency 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 2415_2416delAG; This variant is associated with the following publications: (PMID: 34413315, 32438681, 22798144, 30630528, 29922827, 31447099, 7894493, 29470806, 27062684, 30720243, 16030099, 18821011, 25863477) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 28, 2022	This nonsense variant causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251084 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals diagnosed with hereditary breast and/or ovarian cancer (PMID: 7894493 (1994), 16030099 (2005), 18821011 (2006), 22798144 (2012), 26028024 (2016), 27062684 (2016), 29470806 (2018), 32438681 (2020), 33471991 (2021), 34413315 (2021)). The variant has also been reported in unaffected individuals (PMID: 31447099 (2019), 33471991 (2021)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2022	The c.2296_2297delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2296 to 2297, causing a translational frameshift with a predicted alternate stop codon (p.S766*). This alteration has been previously identified in several breast and/or ovarian cancer kindreds (Friedman LS et al. Nat. Genet. 1994 Dec;8(4):399-404; Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev. 2005 Jul;14(7):1666-71; Golmard L et al. Oncogene 2016 Mar;35(10):1324-7; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). Of note, this alteration is also designated as 2415delAG in some 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	Sep 06, 2023	This variant deletes 2 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 reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 7894493, 8533757, 16030099, 18821011, 22798144, 25863477, 26028024, 32438681, 34072659). This variant has been identified in 12 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). In a large breast cancer case-control study (PMID: 33471991), this variant has been observed in 2/60466 cases and 1/53461 unaffected controls. This variant has been identified in 1/251084 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 25, 2020

- -

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: rs80357780; hg19: chr17-41245250;