17-43047666-C-T

Position:

• chr17-43047666-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.5444G>A​(p.Trp1815*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,614,094 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 (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:32 O:1
• Conservation: PhyloP100: 4.11

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43047666-C-T is Pathogenic according to our data. Variant chr17-43047666-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55580.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43047666-C-T is described in Lovd as [Pathogenic]. Variant chr17-43047666-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5444G>A	p.Trp1815*	stop_gained	22/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5444G>A	p.Trp1815*	stop_gained	22/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 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

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

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: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

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	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 11, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 26, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jan 06, 2025	This sequence change creates a premature translational stop signal (p.Trp1815*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the BRCA1 protein.This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 55580). This variant is also known as 5563G>A. This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 8968102, 20104584, 26187060). It has also been observed to segregate with disease in related individuals. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 29961768, 30209399, 25400221, 26681312, 29446198, 29797126, 15365993, 16267036, 24131973, 28492532, 23469205, 24884479, 20104584, 19996028, 22798144, 32658311, 32039725, 33558524, 27741520, 8968102, 12204006, 22713736, 29998185). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant changes 1 nucleotide in exon 22 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 8968102, 20104584, 22798144, 29998185, 31368036, 32658311, 33558524) and pancreatic cancer (PMID: 29961768). 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 provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 21, 2016	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 30, 2014	- -
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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
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	GeneDx	Dec 10, 2021	Nonsense variant predicted to result in protein truncation 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 (Montagna 1996, Kang 2002, Borg 2010, Jalkh 2012, Fernandes 2016); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5563G>A; This variant is associated with the following publications: (PMID: 29961768, 30209399, 25400221, 26681312, 29446198, 29797126, 15365993, 16267036, 24131973, 28492532, 23469205, 24884479, 20104584, 19996028, 22798144, 32658311, 32039725, 33558524, 27741520, 8968102, 12204006, 22713736, 29998185) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 22, 2018	This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in individuals with suspected hereditary breast and/or ovarian cancer in the published literature (PMID: 29998185 (2018), 29797126 (2018), 26681312 (2015), 20104584 (2010), 8968102 (1996)). Therefore, this individual is at increased risk of developing BRCA1 related cancers. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 25, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 21922593). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 55580). This variant is also known as 5563G>A. This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 8968102, 20104584, 26187060). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1815*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the BRCA1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2016	- -
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	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	ACMG Guidelines 2015 criteria BRCA1 (NM_007294.3: c.5444G>A; p.Trp1815Ter) - The BRCA1 variant p.Trp1815Ter is a known pathogenic nonsense variant in exon 23 and in the functional domain of BRCT2 (aa 1756-1855). BRCA1 contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). This null (nonsense) variant is predicted to encode a truncated non-functional protein which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant was observed in a mutation hotspot region of 21 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300259.2) (PP5 Pathogenic Supporting). 4 pathogenic predictions from DANN, EIGEN, FATHMM-MKL and MutationTaster versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was seen in 4 unrelated patients with a unilateral breast cancer and a strong family history of breast cancer. Therefore, this variant was classified as a Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2024	The p.W1815* pathogenic mutation (also known as c.5444G>A), located in coding exon 21 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5444. This changes the amino acid from a tryptophan to a stop codon within coding exon 21. This mutation has been detected in multiple breast and/or ovarian cancer patients and has been observed to segregate with disease in affected families (Montagna M et al. Cancer Res., 1996 Dec;56:5466-9; Kang HC et al. Hum. Mutat., 2002 Sep;20:235; Seo JH et al. Hum. Mutat., 2004 Oct;24:350; Oktay K et al. J Clin Oncol, 2010 Jan;28:240-4; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Jalkh N et al. Hered Cancer Clin Pract, 2012 Jun;10:7; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Safra T et al. Ann Oncol, 2013 Nov;24 Suppl 8:viii63-viii68; Silva FC et al. BMC Med Genet, 2014 May;15:55; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Kechin AA et al. Bull Exp Biol Med, 2018 May;165:94-100; Matsuo K et al. Gynecol Oncol Rep, 2018 Aug;25:98-101; Bernstein-Molho R et al. Breast Cancer Res Treat, 2019 Nov;178:231-237; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This mutation was also detected in at least one patient with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223). Of note, this alteration is also designated as 5563G>A 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. As such, this alteration is interpreted as a disease-causing mutation -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 28, 2023	This variant changes 1 nucleotide in exon 22 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 8968102, 20104584, 22798144, 29998185, 31368036, 32658311, 33558524) and pancreatic cancer (PMID: 29961768). 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	GeneKor MSA	Jan 01, 2020	This sequence change creates a premature translational stop signal at codon 1815 of the BRCA1 protein. It is expected to result in loss of a portion of the C-terminal BRCT-C functional domain (PMID: 8968102). Truncating variants in BRCA1 gene are known to be pathogenic. This particular variant has been described in the literature in multiple individuals and families affected with hereditary breast and/or ovarian cancer, segregating with disease in a family (PMID: 8968102, 26187060, 20104584). The mutation database ClinVar contains entries for this variant (Variation ID: 55580). -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jan 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 21, 2020	- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

-

- -

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

- -

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.Trp1815X variant was identified in at least 7 of 115778 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Borg 2010, Jalkh 2012, Judkins 2005, Kang 2002, Montagna 1996, Oktay 2010). The variant was also identified in dbSNP (ID: rs80356962) “With untested allele”, HGMD, UMD (2X as a causal variant), and the BIC database (4X with clinical importance). The p.Trp1815X variant leads to a premature stop codon at position 1815, which is predicted to lead to 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. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.93
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356962; hg19: chr17-41199683; COSMIC: COSV58788041;