rs80357524

chr17-43093097-TG-Tchr17-43093097-TG-TGG

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.2433del(p.Lys812ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,370 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. P811P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: -0.115

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 17-43093097-TG-T is Pathogenic according to our data. Variant chr17-43093097-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37469.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093097-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43093097-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2433del	p.Lys812ArgfsTer3	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2433del	p.Lys812ArgfsTer3	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250608 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000274 AC: 4 AN: 1461370 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 29, 2018	This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer (PMID: 25863477, 16455195, 25371446, 23233716). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/245,372) and thus is presumed to be rare. Based on the available evidence, the c.2433delC (p.Lys812ArgfsTer3) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 29, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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	Baylor Genetics	Oct 22, 2023	- -
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	Division of Medical Genetics, University of Washington	Jun 11, 2020	This variant causes a frameshift that leads to a premature termination codon. This variant is predicted to cause loss of normal protein either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported in a number of women with breast and/or ovarian cancer (Ahn et al. 2007; Torres-Mejia et al. 2015; and Weitzel et al. 2013). Based on this evidence we interpret this variant as pathogenic. PS4; PVS1 -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2023	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 30350268 (2018), 29240602 (2018), 23233716 (2013), 22217648 (2012), 20104584 (2010)). The frequency of this variant in the general population, 0.000008 (2/250608 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2552delC; This variant is associated with the following publications: (PMID: 22798144, 25628955, 20104584, 29673794, 34490083, 29922827, 28888541, 23233716, 19241424, 17591843, 17100994, 16949048, 16455195, 16030099, 19499246, 25863477, 16685647, 22217648, 19967274, 25371446, 26402875, 28985766, 26295337, 30350268, 30309222, 17925560, 16267036, 30274973, 30720243, 32868804, 28111427, 34645131) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	The BRCA1 c.2433del; p.Lys812ArgfsTer3 variant (rs80357524), also reported as 2552delC, has been described in multiple individuals affected with breast and/or ovarian cancer and is a recurrent variant in Hispanic and Korean populations (Ahn 2007, Kim 2012, Tung 2015, Vogel 2007, Weitzel 2005). It is reported as a pathogenic variant by multiple sources in ClinVar (Variation ID: 37469) and is described on only 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Ahn S et al. BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations. Cancer Lett. 2007 Jan 8;245(1-2):90-5. Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012 Aug;134(3):1315-26. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Vogel K et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol. 2007 Oct 10;25(29):4635-41. Weitzel J et al. Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1666-71. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2022	- -
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	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Lys812Argfs*3) 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 (rs80357524, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16030099, 22798144, 23233716). This variant is also known as 2552delC. ClinVar contains an entry for this variant (Variation ID: 37469). 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	Jun 26, 2018	Variant summary: BRCA1 c.2433delC (p.Lys812ArgfsX3) 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. The variant allele was found at a frequency of 8.1e-06 in 245706 control chromosomes (gnomAD). The variant, c.2433delC, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Han_2006, Weitzel_2005, Lim_2009, Vogel_2007, John_2007, Mgbemena_2017). 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. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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	May 11, 2021	The c.2433delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2433, causing a translational frameshift with a predicted alternate stop codon (p.K812Rfs*3). This mutation has been reported in numerous HBOC patients and families (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Kim BY et al. Biochem Biophys Res Commun, 2006 Oct;349:604-10; Han SH et al. Clin Genet, 2006 Dec;70:496-501; Ahn SH et al. Cancer Lett, 2007 Jan;245:90-5; Vogel KJ et al. J Clin Oncol, 2007 Oct;25:4635-41; John EM et al. JAMA, 2007 Dec;298:2869-76; Hall MJ et al. Cancer, 2009 May;115:2222-33; Lim MC et al. J Cancer Res Clin Oncol, 2009 Nov;135:1593-9; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Jang JH et al. J. Hum. Genet., 2012 Mar;57:212-5; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Weitzel JN et al. J Clin Oncol, 2013 Jan;31:210-6; Tung N et al. Cancer, 2015 Jan;121:25-33; Torres-Mejía G et al, 2015 Mar;24:498-505; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68; Choi MC et al. Int J Gynecol Cancer, 2015 Oct;25:1386-91; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with pancreatic cancer and acute myeloid leukemia (Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Kim B et al. Sci Rep, 2020 08;10:14297). Of note, this alteration is also designated as 2552delC 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	Dec 27, 2022	This variant deletes 1 nucleotide 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 over 10 individuals affected with breast and ovarian cancer (PMID: 16030099, 16685647, 16949048, 16455195, 17925560, 18159056, 19499246, 20104584, 22798144, 25186627, 25371446, 26402875, 33471991, 34063308) and has been observed to be a recurrent mutation in Latino and Korean populations (PMID: 17925560, 22798144, 26402875). This variant has been identified in 2/250608 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. -

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

Dec 08, 2021

- -

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.Lys812ArgfsX3 deletion variant was identified in at least 13 of 117374 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer, and was not identified in 334 control chromosomes from healthy individuals (Borg 2010, Han 2006, Judkins 2005, Weber 2006, Weitzel 2005). The variant was also identified in dbSNP (ID: rs80357524 ) “With pathogenic allele, HGMD, LOVD, COSMIC, the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project (derived from Myriad reports); classified as pathogenic by Ambry Genetics), the BIC database (11X with clinical importance, classified as pathogenic), and UMD (1X as a causal variant). The p.Lys812ArgfsX3deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 812 and leads to a premature stop codon 3 codons downstream. 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. -

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: rs80357524; hg19: chr17-41245114;