17-43071225-G-C

Position:

• chr17-43071225-G-C

Variant summary

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

The ENST00000357654.9(BRCA1):​c.4689C>G​(p.Tyr1563Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y1563Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:42 U:1
• Conservation: PhyloP100: 0.723

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 17-43071225-G-C is Pathogenic according to our data. Variant chr17-43071225-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 37607.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071225-G-C is described in Lovd as [Pathogenic]. Variant chr17-43071225-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4689C>G	p.Tyr1563Ter	stop_gained	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4689C>G	p.Tyr1563Ter	stop_gained	15/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250704 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135612

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:42 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:19

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 15, 2024	The BRCA1 c.4689C>G (p.Tyr1563Ter) change creates a premature stop codon in exon 15. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay, and other protein truncation variants have been observed in exon 15. This variant has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been observed in individuals with a personal and/or family history of breast and ovarian cancer and has been found to segregate with disease in affected individuals (PMID: 8554067, 20727672, 23110154, 25066507, 27167707). This variant has not been reported in the literature in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 06, 2017	The c.4689C>G (p.Tyr1563*) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 8554067, 23110154]. This variant creates a premature stop codon at amino acid position 1563 of the BRCA1 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant is thus classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 21, 2021	- -
Pathogenic, criteria provided, single submitter	research	Snyder Lab, Genetics Department, Stanford University	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2016	- -
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	Institute of Human Genetics, University of Leipzig Medical Center	Jun 27, 2023	Criteria applied: PVS1,PS4,PM2_SUP -

not provided Pathogenic:13 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 28, 2019	This variant 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: 29907814 (2018), 28324225 (2017), 8554067 (1996)). The frequency of this variant in the general population, 0.0000088 (1/113148 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	Eurofins Ntd Llc (ga)	May 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2023	The BRCA1 c.4689C>G; p.Tyr1563Ter variant (rs80357433), also known as 4808C>G, is reported in the literature in multiple individuals and families affected with hereditary breast and ovarian cancer (Pern 2012, Rebbeck 2018, Schneegans 2012, Serova 1996). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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: Pern F et al. Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. PLoS One. 2012;7(10):e47993. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Schneegans SM Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 Jun;11(2):181-8. Serova O et al. A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am J Hum Genet. 1996 Jan;58(1):42-51. -
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	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2022	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 (Serova 1996, Shih 2002, Turkovic 2010, Schneegans 2012, Wong-Brown 2015, Nguyen-Dumont 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 4808C>G; This variant is associated with the following publications: (PMID: 27167707, 30128899, 29422015, 30551077, 34657373, 29922827, 30040829, 28888541, 11844822, 8554067, 22160602, 23110154, 25556971, 24830819, 25682074, 26843898, 25948282, 25085752, 29339979, 28324225, 29907814, 29446198, 30487145, 30216591, 30322717, 20807450, 32072338, 30787465, 30612635, 29625052, 31447099, 35596902, 36367610, 36171877) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2024	PM5_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change creates a premature translational stop signal at codon 1563 (p.Tyr1563*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with hereditary breast and ovarian cancer (PMID: 8554067, 23110154, 25066507, 20727672, 27167707). This sequence change is also known as 4808C>G in the literature. This particular variant has been described in the mutation database ClinVar (Variation ID: 37607) as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2016	The p.Tyr1563X variant in BRCA1 has been reported in >50 individuals with BRCA1-associated cancers (Breast cancer information core (BIC) database, Serova 1996, Pern 2012, Janavičius 2014, Koczkowska 2016) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1563, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Additionally, the p.Tyr1563X variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA Expert Panel (SCV000282332.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon its predicted impact to the protein, absence from controls, and numerous reports in affected individuals. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Tyr1563*) 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 (rs80357433, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 8554067, 20727672, 23110154, 25066507, 27167707). It has also been observed to segregate with disease in related individuals. This variant is also known as 4808C>G. ClinVar contains an entry for this variant (Variation ID: 37607). 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	Jul 23, 2020	Variant summary: BRCA1 c.4689C>G (p.Tyr1563X) 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 4e-06 in 250704 control chromosomes (gnomAD). c.4689C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Alsop_2012, Bergman_2005, Couch_2015, 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 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. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This variant changes 1 nucleotide in exon 15 of the BRCA1 gene, creating a premature translation stop signal. RNA analyses have shown that this variant leads to an absence of RNA transcript and protein product (PMID: 8554067, 12393792). This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 8554067, 11844822, 15951958, 20727672, 20807450, 22160602, 22711857, 22762150, 23110154, 25066507, 25452441, 27167707, 29339979, 33471991). This variant has been identified in 1/250704 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	Ambry Genetics	Nov 29, 2021	The p.Y1563* pathogenic mutation (also known as c.4689C>G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4689. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Iyevleva AG et al. Cancer Lett. 2010 Dec;298:258-63; Schneegans S et al. Fam. Cancer. 2012 Jun;11:181-8; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Pern F et al. PLoS One. 2012;7:e47993; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620), and a history weighing algorithm classified it as pathogenic (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). One study demonstrated that this mutation triggers nonsense mediated decay (NMD) and results in less than half the amount of BRCA1 mRNA compared to wild-type (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14). Of note, this alteration is also designated as 4808C>G 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. -

BRCA1-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 08, 2024

This variant changes 1 nucleotide in exon 15 of the BRCA1 gene, creating a premature translation stop signal. RNA analyses have shown that this variant leads to an absence of RNA transcript and protein product (PMID: 8554067, 12393792). This variant has been detected in multiple individuals and families affected with breast and ovarian cancer (PMID: 8554067, 11844822, 15951958, 20727672, 20807450, 22160602, 22711857, 22762150, 23110154, 25066507, 25452441, 27167707, 29339979, 33471991). This variant has been identified in 1/250704 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. -

BRCA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2023

The BRCA1 c.4689C>G variant is predicted to result in premature protein termination (p.Tyr1563*). This variant has previously been reported to be causative for hereditary breast and ovarian cancer (Serova et al. 1996. PubMed ID: 8554067; Pern et al. 2012. PubMed ID: 23110154). This variant has also been recorded as a breast cancer associated variant within the Breast Cancer Information Core (BIC) database (http://research.nhgri.nih.gov/projects/bic/) and as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37607/). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41223242-G-C). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.23	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.96
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357433; hg19: chr17-41223242;