rs80357919

chr17-43094684-ATGAG-A

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.843_846del(p.Ser282TyrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,474 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. S281S) 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 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:31
• Conservation: PhyloP100: 4.22

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 17-43094684-ATGAG-A is Pathogenic according to our data. Variant chr17-43094684-ATGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 17683.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094684-ATGAG-A is described in Lovd as [Pathogenic]. Variant chr17-43094684-ATGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.843_846del	p.Ser282TyrfsTer15	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.843_846del	p.Ser282TyrfsTer15	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 03, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 28, 2021	- -
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	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 28, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR, PM2_SUP -
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	Department of Medical Genetics, Oslo University Hospital	Jun 28, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 13, 2023	- -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Ser282TyrfsX15 variant has been reported in 25 of 3463 probands with breast or ovarian cancer (Anton-Culver_2000_10882857, Capalbo_2006_16760289, Wagner_1998_9663595, Zhang_2011_21324516, Machackova_2008_18489799, Janezic_1999_10196379, http://research.nhgri.nih.gov/bic/). In addition, The p.Ser282TyrfsX15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 282 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the BRCA1 gene, which makes it highly likely that the p.Ser282TyrfsX15 variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	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; Reported in numerous individuals with personal and/or family histories of breast and/or ovarian cancer (Wagner 1998, Janezic 1999, Stegel 2011, Zhang 2011, Pern 2012, Song 2014, Muendlein 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 962del4 and 962_965delCTCA; This variant is associated with the following publications: (PMID: 10196379, 9663595, 21324516, 23110154, 22366370, 21232165, 23397983, 23635950, 24797986, 24728189, 27221827, 25971625, 27533253, 26306726, 25066507, 18489799, 11179017, 27062684, 29339979, 28324225, 31159747, 32341426, 26681312) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.843_846delCTCA), causing a frameshift after codon 282 and the creation of a premature translation stop signal 15 amino acid residues later- p.(Ser282Tyrfs). This is expected to result in an absent or disrupted protein product.Truncating variants in BRCA1 are known to be pathogenic. This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747).This mutation has been described in the mutation database ClinVar (Variation ID: 17683). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	Mar 25, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17683). This variant is also known as 962del4. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9663595, 10196379, 17319787, 21203900, 21324156, 23110154). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser282Tyrfs*15) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Ser282TyrfsX15 variant in BRCA1 has been reported in 23 individuals with BRCA1-related cancers (first published by Wagner 1998 PMID: 9663595). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 17683). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 282 and leads to a premature termination codon 15 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/or ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -
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	Apr 30, 2021	Variant summary: BRCA1 c.843_846delCTCA (p.Ser282TyrfsX15) 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 254112 control chromosomes (gnomAD and publication data). c.843_846delCTCA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Wagner_1998, Janezic_1999, Judkins_2005, Song_2014, 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. Twelve ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Aug 01, 2000	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2022	The c.843_846delCTCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of four nucleotides at positions 843 to 846, causing a translational frameshift with a predicted alternate stop codon (p.S282Yfs*15). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Janezic SA et al. Hum. Mol. Genet. 1999;8:889-97; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Wagner TM et al. Int. J. Cancer. 1998 July;77:354-60; Tihomirova L et al. Adv Med Sci. 2014 Mar;59:114-9; Pern F et al. PLoS ONE. 2012 Oct;7:e47993; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Dobricic J et al. J. Hum. Genet. 2013 Aug;58:501-7; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this mutation is also designated as 962del4 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Jan 15, 2020	This variant deletes 4 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 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. -

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

Jul 27, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 13, 2024

Criteria applied: PVS1,PM5_STR,PM2_SUP -

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: rs80357919; hg19: chr17-41246701;