rs80357366

Positions:

• chr17-43074403-C-A
• chr17-43074403-C-G
• chr17-43074403-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.4603G>T​(p.Glu1535Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,192 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. E1535E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: -0.454

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 17-43074403-C-A is Pathogenic according to our data. Variant chr17-43074403-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55236.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074403-C-A is described in Lovd as [Pathogenic]. Variant chr17-43074403-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4603G>T	p.Glu1535Ter	stop_gained	14/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4603G>T	p.Glu1535Ter	stop_gained	14/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000482

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 25, 2012	- -
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	All of Us Research Program, National Institutes of Health	Dec 11, 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with early-onset and/or familial breast cancer (PMID: 11606101, 22811390, 23096355, 26183948, 28503720). 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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 05, 2023	PVS1, PS4, PM2 -
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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 02, 2018	This c.4603G>T (p.Glu1535*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant is absent in the general population according to the gnomAD database. It has been reported in several unrelated patients with breast cancer or ovary cancer [PMID: 11606101, 22811390].Therefore, the c.4603G>T (p.Glu1535*) variant in the BRCA1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2016	Variant Summary: The variant in interest, c.4603G>T, is a nonsense mutation that leads to a premature termination at codon 1535. This variant has been reported in the literature and reputable databases at least 15 times and was not identified in large and broad ExAC control cohort. This variant is located in a close proximity to other known pathogenic variants, such as c.4609C>T (p.Gln1537X), c.4612C>T (p.Gln1538X), c.4618G>T (p.Glu1540X) and c.4621G>T (p.Glu1541X). These variants have been reported in UMD, BIC and HGMD at least 7 times with biological significance "5 - Causal", indicating that the variant in interest is located in a mutational hot spot. The variant in interest shows very strong evidence for pathogenicity: it is a truncating variant, located in a mutational hot spot and is absent from controls (ESP and 1000G). Taken together, this variant has been classified as a 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Glu1535X variant in BRCA1 has been previously reported in at least 9 individuals with BRCA2-associated cancers (Schorge 2001 PMID:11606101, Ozcelik 2003 PMID:12920083, Pennington 2013 PMID:22811390, Dodova 2015 PMID:26183948, Rummel 2017 PMID:28503720, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, ClinVar Variation ID 55236) and in at least 3 individuals with a family history of breast and ovarian cancer (HBOC) that had undergone clinical genetic testing (Barrington 2018 PMID: 29486991, Rebbeck 2018 PMID: 29446198). It has also been identified in 0.005% (2/41454) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This frequency is low enough to be consistent with the frequency of HBOC in the general population. This nonsense variant leads to a premature termination codon at position 1535, 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 individuals with HBOC. Additionally, this variant was classified as pathogenic on Sept 08, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300141.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 10, 2023	Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 55236). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and uterine cancer (PMID: 11606101, 22811390, 26183948, 28503720). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1535*) 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). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 02, 2023	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23096355, 29486991, 25525159, 11606101, 26183948, 28503720, 28049106, 22811390, 28127413, 29446198, 31209999, 31447099) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2021	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 individuals affected with early-onset and/or familial breast cancer (PMID: 11606101, 22811390, 23096355, 26183948, 28503720). 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	Ambry Genetics	May 24, 2022	The p.E1535* pathogenic mutation (also known as c.4603G>T), located in coding exon 13 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4603. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This mutation has been reported in several individuals with breast and/or ovarian cancer and one patient with breast and serous mixed endometrioid cancers (Schorge JO et al. Gynecol. Oncol. 2001 Nov;83:383-7; Pennington KP et al. Cancer. 2013 Jan;119:332-8; Rummel S et al. Breast Cancer Res. Treat. 2013 Jan;137:119-25; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164:593-601; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Barrington DA et al. Gynecol. Oncol. 2018 05;149:337-340). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.038	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;N;N;N;N
Vest4		0.86
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs80357366; hg19: chr17-41226420;