17-43093569-CTTTT-CTTT

Position:

• chr17-43093569-CTTTT-CTTT

Variant summary

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

The NM_007294.4(BRCA1):​c.1961del​(p.Lys654SerfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,680 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. K654K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:36
• Conservation: PhyloP100: -0.184

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 17-43093569-CT-C is Pathogenic according to our data. Variant chr17-43093569-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37438.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093569-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093569-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093569-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43093569-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1961del	p.Lys654SerfsTer47	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1961del	p.Lys654SerfsTer47	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152002 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

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250730 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135562

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461678 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727126

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

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:36

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 11, 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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2073delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over 20 individuals and families affected with breast, ovarian and endometrial cancer (PMID: 7493024, 11179017, 11956590, 14517958, 14760071, 16455195, 17645508, 20727672, 22711857, 22798144, 23479189, 25256238, 28324225, 33471991; Leiden Open Variation Database DB-ID BRCA1_000177) and one individual each affected with prostate cancer (PMID: 31214711) and hemangioblastoma (PMID: 24884479). This variant has been identified in 3/282102 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, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 27, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 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. -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 27, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	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 reported as a recurrent variant in Spanish populations (Gayther 1995, Risch 2001, Diez 2003, de Juan Jimenez 2013, Abugattas 2015, Couch 2015, de Juan 2015, Kang 2015); 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; This variant is associated with the following publications: (PMID: 25452441, 11595708, 27376475, 16455195, 11956590, 26026974, 29310832, 7493024, 23633455, 12955716, 22798144, 11179017, 20727672, 17645508, 14517958, 16234499, 25256238, 25863477, 23479189, 26295337, 27533253, 27167707, 28324225, 29928469, 28831036, 29907814, 30606148, 30720863, 28176296, 30720243, 30014164, 30322717, 31090900, 29625052, 26689913, 30350268, 31214711, 33654310, 32341426, 31825140) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Lys654Serfs*47) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast, ovarian, and endometrial cancer (PMID: 7493024, 12955716, 17645508, 23633455, 26026974). This variant is also known as 2073delA and 2080delA. ClinVar contains an entry for this variant (Variation ID: 37438). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 03, 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	GeneKor MSA	Jan 01, 2020	This variant is a single base pair deletion at amino acid residue 654 of the BRCA1 gene. It results in a frame-shift, creating a new stop codon after 47 amino acids, thus resulting in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic. This variant is also known as 2073delA and 2080delA and has been reported in the literature in patients affected with breast, ovarian, and endometrial cancer (PMID: 7493024, 12955716, 17645508). The mutation database ClinVar contains entries for this variant (Variation ID: 37438). -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1961delA (p.Lys654SerfsTer47) variant (also commonly referred to as c.2080delA) results in a frameshift, and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys654SerfsTer47 variant has been identified in a heterozygous state in 29 cases of breast or ovarian cancer (Gayther et al. 1995; Risch et al. 2001; Curci et al. 2002; Diez et al. 2003; Martinez-Ferrandis et al. 2003; Ahn et al. 2007; Kwon et al. 2008; Iyevleva et al. 2010; Kim et al. 2012; Kang et al. 2015; de Juan Jiminez et al. 2013; George et al. 2013; Abugattas et al. 2014; Silva et al. 2014). The variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (Non-Finnish) population of the Exome Aggregation Consortium Project but this is based on one allele so the variant is presumed to be rare. Most variants in the BRCA1 gene that have been shown to be associated with breast and ovarian cancer are frameshift variants resulting in a non-functional protein. Based on the potential impact of frameshift variants and the available evidence, the p.Lys654SerfsTer47 variant is classified as pathogenic for hereditary breast and ovarian cancer syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2020	Variant summary: BRCA1 c.1961delA (p.Lys654SerfsX47) 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 8e-06 in 250730 control chromosomes (gnomAD). c.1961delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Gayther_1995, Grushko_2004, Alsop_2012, de Juan_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Sixteen ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic, while one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. 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	Jun 21, 2024	The c.1961delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.K654Sfs*47). This mutation has been reported numerous times in the literature in breast and breast/ovarian cancer families, including in a case of male breast cancer (Gayther SA et al. Nat. Genet. 1995 Dec;11(4):428-33; George J et al. Clin. Cancer Res. 2013 Jul;19(13):3474-84; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12(4):767-77; Abugattas J et al. Clin. Genet. 2015 Oct;88(4):371-5; de Juan I et al. Fam. Cancer, 2015 Dec;14:505-13; Meisel C et al. Arch Gynecol Obstet. 2017 May;295(5):1227-1238). Of note, this alteration is also designated as 2080delA 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	Sep 20, 2023	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2073delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over 20 individuals and families affected with breast, ovarian and endometrial cancer (PMID: 7493024, 11179017, 11956590, 14517958, 14760071, 16455195, 17645508, 20727672, 22711857, 22798144, 23479189, 25256238, 28324225, 33471991; Leiden Open Variation Database DB-ID BRCA1_000177) and one individual each affected with prostate cancer (PMID: 31214711) and hemangioblastoma (PMID: 24884479). This variant has been identified in 3/282102 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. -

Infiltrating duct carcinoma of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Sep 14, 2017

- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

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.Lys654Serfs*47 variant was identified in 5 of 1160 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Al-Mulla 2008, de Juan 2015, Diez 2003). The variant was also identified in dbSNP (ID: rs80357522), ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and sixteen other submitters), and in LOVD 3.0 (58X ).The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1961del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 654 and leads to a premature stop codon at position 700. 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 BRCA1 associated cancers 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, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Nov 30, 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: rs80357522; hg19: chr17-41245586;