rs80356991

Positions:

• chr17-43104136-C-A
• chr17-43104136-C-G
• chr17-43104136-C-T

Variant summary

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

The NM_007294.4(BRCA1):​c.427G>T​(p.Glu143Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,442 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: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:26 U:1
• Conservation: PhyloP100: 1.94

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 17-43104136-C-A is Pathogenic according to our data. Variant chr17-43104136-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37581.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104136-C-A is described in Lovd as [Pathogenic]. Variant chr17-43104136-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.427G>T	p.Glu143Ter	stop_gained	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.427G>T	p.Glu143Ter	stop_gained	6/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461442 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727026

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PP3; PS3; PP1_Strong; PM3_Supporting -
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	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent protein product and BRCA1 mRNA levels is severely reduced in carrier RNA (PMID: 12393792). A functional study has reported that this variant impacts BRCA1 in ubiquitin E3 ligase assays (PMID: 25823446). This variant has been reported in at least 20 individuals and families affected with breast and ovarian cancer (PMID: 9333265, 12393792, 20104584, 23961350, 23884708, 24504028, 26681312, 26833046, 33471991; Leiden Open Variation Database DB-ID BRCA1_000082; Color internal data) and it is a suspected founder mutation in the Irish population (PMID: 23199084). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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 Pathogenic:8 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	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 several individuals and families with breast and/or ovarian cancer, and has been reported to be an Irish pathogenic founder variant (van Orsuow 1999, Meyer 2003, van der Hout 2006, Janavicius 2010, Solano 2012, Cunningham 2014, Walsh 2015); Not observed 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 546G>T; This variant is associated with the following publications: (PMID: 32719484, 32338768, 9333265, 29961768, 25525159, 30093976, 29446198, 29506128, 25503966, 18680205, 29422015, 28873162, 25085752, 26733283, 27836010, 28127413, 25673166, 26681312, 25823446, 12938098, 23961350, 20104584, 16683254, 23199084, 24504028, 10528853, 22009639) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 13, 2020	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals affected with breast cancer and ovarian cancer in the published literature (PMID: 27836010 (2016), 24504028 (2014), 23961350 (2012), 22009639 (2012), 20104584 (2010)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 20, 2022	PP5, PM2, PS3, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2020	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.427G>T, which results in the creation of a premature stop codon at amino acid position 143, p.Glu143*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. This pathogenic sequence change, also reported as c.546G>T in the literature, has previously been described in individuals with breast and/or ovarian cancer, and pancreatic cancer (PMIDs: 9333265, 22009639, 24504028, 20104584, 23961350, 29961768). The p.Glu143* change has not been described in population databases (gnomAD, ExAC). These collective evidences suggest that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	BRCA1: PVS1, PM2, PS4:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2017	The BRCA1 c.427G>T, p.Glu143Ter variant (rs80356991) has been reported in patients with breast or ovarian cancer (Shattuck-Eidens 1997, Cunningham 2014), and listed as pathogenic on ClinVar (Variation ID: 37581). The predicted truncated BRCA1 protein lacks homologous recombination activity when expressed in yeast (Caligo 2009). The variant is not been observed in the general population databases, such as the 1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the p.Glu143Ter variant is classified as pathogenic. References: Caligo M et al. (2009) Hum Mutat. A yeast recombination assay to characterize human BRCA1 missense variants of unknown pathological significance. 30(1):123-33. Cunningham J et al (2014). Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 4:4026. Shattuck-Eidens D et al (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 278(15):1242-50. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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	Oct 14, 2019	The p.Glu143X variant in BRCA1 has been reported in >15 individuals with BRCA1-related cancers (Shattuck-Eidens 1997, Caligo 2009, Cunningham 2014, Susswein 2016, Lowery 2018, Yurgelun 2019, BIC database). It was absent from large population studies. This frameshift variant leads to a premature termination codon at position 143, 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 Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Glu143*) 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 and/or ovarian cancer (PMID: 9333265, 20104584, 22009639, 23961350, 24504028). This variant is also known as 546G>T and E143X. ClinVar contains an entry for this variant (Variation ID: 37581). 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	Aug 31, 2020	Variant summary: BRCA1 c.427G>T (p.Glu143X) 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 251024 control chromosomes. c.427G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Solano_2013, Judkins_2005, Evans_2003, Nielsen_2016). These data indicate that the variant is very likely to be associated with disease. Nine 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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2021	The p.E143* pathogenic mutation (also known as c.427G>T), located in coding exon 5 of the BRCA1 gene, results from a G to T substitution at nucleotide position 427. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This mutation has been reported in several individuals diagnosed with breast and/or ovarian cancer (Perrin-Vidoz L et al. Hum. Mol. Genet. 2002 Nov;11:2805-14; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This alteration has been reported to co-occur with the BRCA2 c.8730delT mutation in a Caucasian patient from Denmark (Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). This alteration has also been reported as a possible Irish founder mutation, after the author noted that it accounted for 22% of all HBOC individuals in an Irish population (Janaviius R. EPMA J. 2010 Sep;1:397-412). It has since been reported in multiple individuals from Western Ireland (McVeigh TP et al. Ir. J. Med. Sci. 2014 Jun;183:199-206). Of note, this alteration is also designated as 546G>T 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	curation	Sema4, Sema4	May 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2024	This variant changes 1 nucleotide in exon 6 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent protein product and BRCA1 mRNA levels is severely reduced in carrier RNA (PMID: 12393792). A functional study has reported that this variant impacts BRCA1 in ubiquitin E3 ligase assays (PMID: 25823446). This variant has been reported in at least 20 individuals and families affected with breast and ovarian cancer (PMID: 9333265, 12393792, 20104584, 23961350, 23884708, 24504028, 26681312, 26833046, 33471991; Leiden Open Variation Database DB-ID BRCA1_000082; Color internal data) and it is a suspected founder mutation in the Irish population (PMID: 23199084). This variant has been identified in 94 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). 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. -

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	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.62	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;N;N;N;N
Vest4		0.93
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs80356991; hg19: chr17-41256153;