17-43074482-C-T

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.4524G>A(p.Trp1508Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,826 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:27 U:1
• Conservation: PhyloP100: -0.0220

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 17-43074482-C-T is Pathogenic according to our data. Variant chr17-43074482-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55221.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074482-C-T is described in Lovd as [Pathogenic]. Variant chr17-43074482-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4524G>A	p.Trp1508Ter	stop_gained	14/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4524G>A	p.Trp1508Ter	stop_gained	14/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

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, 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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 02, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 04, 2024	This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 17, 2016	- -

not provided Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2023	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 (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce et al., 2015); Not observed at 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 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2023	PP5, PM2, PVS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221). -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2021	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2020	Variant summary: BRCA1 c.4524G>A (p.Trp1508X) 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 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). 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 clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Trp1508*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2019	The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is 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 ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2022	The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A 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	Oct 19, 2023	This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 16, 2019

The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), and is absent from general population databases (Exome Variant Server, 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: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. 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. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 03, 2023

- -

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

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	33
Dann	Benign	0.97
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.023	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;N;N;N;N;N
Vest4		0.85
GERP RS		1.6

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: rs80356885; hg19: chr17-41226499;