rs80357711

chr17-43091495-CT-C

Variant summary

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

The NM_007294.4(BRCA1):c.4035del(p.Glu1346LysfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:35
• Conservation: PhyloP100: -0.773

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 17-43091495-CT-C is Pathogenic according to our data. Variant chr17-43091495-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37560.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091495-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43091495-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4035del	p.Glu1346LysfsTer20	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4035del	p.Glu1346LysfsTer20	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152228 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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251112 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135720

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461168 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726812

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: 0.00000990

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 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 4153delA and 4154delA in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with breast and ovarian cancer (PMID: 20345474, 24770866, 29785153, 30040829) and is known to be a founder mutation in the Baltic Population (PMID: 23274591). This variant also has been detected in a breast cancer case-control meta-analysis in 11/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000791). This variant has been identified in 12/282514 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	Mar 01, 1996	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 14, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Glu1346LysfsX20 deletion variant was identified in 176 of 22934 proband chromosomes (frequency: 0.008) from individuals with prostate cancer, breast cancer, ovarian cancer, or other gynaecological tumours, and was present in 3 of 11336 control chromosomes (frequency: 0.0003) (Bayraktar 2012, Bogdanova 2010, Cybulski 2013, Elsakov 2010, Gayther 1996 8644703, Jakubowska 2008, Plakhins 2011, Tikhomirova 2005, Uglanitsa 2010). The variant is described in the literature as a founder mutation in Slavic and Baltic countries, including Poland, Belarus, Latvia, Russia, and Lithuania (Bogdanova 2010, Cybulski 2013, Elsakov 2010, Ozolina 2009, Uglanitsa 2010). The variant was also identified in dbSNP (ID: rs80357711) “With pathogenic allele”, HGMD, UMD (2X as a causal variant), and the BIC database (51X as a variant with clinical importance). The p.Glu1346LysfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1346 and leads to a premature stop codon 20 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. -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 19, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 04, 2019	- -
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	Institute of Human Genetics, University of Leipzig Medical Center	Nov 15, 2023	Criteria applied: PVS1,PS4,PM5_STR -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 26, 2021	The BRCA1 c.4035delA; p.Glu1346LysfsTer20 variant (rs80357711), also known as 4153del or 4154del, is reported in several individuals affected with breast and ovarian cancer and is described as a pathogenic founder variant in the European population (Bogdanova 2010, Elsakov 2010, Plakhins 2011). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37560) and is listed in the non-Finnish European population with an allele frequency of 0.009% (12/129,020 alleles) in the Genome Aggregation Database. 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 to be pathogenic. References: Bogdanova NV et al. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet. 2010 Oct;78(4):364-72. PMID: 20569256. Elsakov P et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010 Oct;78(4):373-6. PMID: 20345474. Plakhins G et al. Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia. BMC Med Genet. 2011 Oct 27;12:147. PMID: 22032251. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	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 is reported as a pathogenic founder variant in several eastern European countries (Gayther 1996, Bogdanova 2010, Janavicius 2013, Szwiec 2015, Synowiec 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4153delA or 4154delA; This variant is associated with the following publications: (PMID: 29684080, 29339979, 8644703, 26779294, 23274591, 26928677, 29492181, 28166811, 23149842, 22032251, 22009639, 20345474, 20507347, 20569256, 24504028, 24797986, 20223023, 24528374, 26753012, 26843898, 27836010, 26681312, 29723101, 28831036, 29719582, 29785153, 29086229, 28279176, 30720243, 30322717, 31159747, 29625052, 26689913, 27535533) -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 29, 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, 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	Aug 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	BRCA1: PVS1, PS4:Moderate -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 21, 2022	Variant summary: BRCA1 c.4035delA (p.Glu1346LysfsX20) 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 2.8e-05 in 253150 control chromosomes. c.4035delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Gorski_2004, Bogdanova_2010, 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. 21 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Glu1346Lysfs*20) 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 (rs80357711, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15591272, 20345474, 20569256, 22032251, 23199084). This variant is also known as 4153delA and 4154delA. ClinVar contains an entry for this variant (Variation ID: 37560). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2019	The p.Glu1346LysfsX20 variant in BRCA1 has been reported in >100 individuals with BRCA1-associated cancers and is a known eastern European founder mutation (Janavicius 2013, Tihomirova 2014, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has been identified in 12/129020 (0.009%) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1346 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Morevoer, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282321.1). In summary, the p.Glu1346LysfsX20 variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4. -
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	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 09, 2021	This sequence change deletes 1 nucleotide from exon 11 of the BRCA1 mRNA (c.4035delA), causing a frameshift after codon 1346 and the creation of a premature translational stop signal 20 amino acid residues later (p.Glu1346Lysfs*20) This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic.This variant is also known as 4153delA and 4154delA in the international literature and is a known common cause of breast and ovarian cancer in individuals from Eastern Europe (PMID: 22032251 ,23199084).This mutation has been described in the mutation database ClinVar (Variation ID: 37560). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 20, 2023	_x000D_ Criteria applied: PVS1, PS4 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 05, 2022	The c.4035delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4035, causing a translational frameshift with a predicted alternate stop codon (p.E1346Kfs*20). This mutation has been reported in numerous cases of breast and ovarian cancer (Gayther SA et al. Am. J. Hum. Genet. 1996 Mar;58:451-6; Elsakov P et al. Clin. Genet. 2010 Oct;78:373-6; Uglanitsa N et al. Clin. Genet. 2010 Oct;78:377-80; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Maxwell KN et al. Nat. Commun. 2017 08;8:319; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Yehia L et al. PLoS Genet., 2018 04;14:e1007352; Kowalik A et al. PLoS ONE, 2018 Jul;13:e0201086; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165). Furthermore, this mutation is regarded as a founder mutation of Baltic origin, with the highest observed frequency in Lithuania (Janavicius R et al. Eur. J. Med. Genet. 2013 Mar;56:125-30). Of note, this alteration is also designated as 4154delA and 4153delA 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	Jan 09, 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 4153delA and 4154delA in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with breast and ovarian cancer (PMID: 20345474, 24770866, 29785153, 30040829) and is known to be a founder mutation in the Baltic Population (PMID: 23274591). This variant also has been detected in a breast cancer case-control meta-analysis in 11/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000791). This variant has been identified in 12/282514 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, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

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: rs80357711; hg19: chr17-41243512;