rs28897686

chr17-43091783-C-Achr17-43091783-C-Gchr17-43091783-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.3748G>T(p.Glu1250Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,836 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. E1250E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 0.505

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 17-43091783-C-A is Pathogenic according to our data. Variant chr17-43091783-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17672.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091783-C-A is described in Lovd as [Pathogenic]. Variant chr17-43091783-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3748G>T	p.Glu1250Ter	stop_gained	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3748G>T	p.Glu1250Ter	stop_gained	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251234 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:13

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -
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 10 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 observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 7894491, 12497638, 18413725, 20104584, 21120943, 22469508, 22486713, 24504028, 26681312, 26845104, 27062684, 27767231; DOI: 10.21203/rs.3.rs-591403/v1, 10.21203/rs.3.rs-122156/v1) and also colon and stomach cancer and low-grade glioma (PMID: 26689913, 26681312). This variant has been identified in 80 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/) and in a breast cancer case-control meta-analysis in 4/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001240). This variant has been identified in 2/251234 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 05, 2012	- -
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, criteria provided, single submitter	clinical testing	Counsyl	Jun 17, 2015	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2023	The BRCA1 c.3748G>T (p.Glu1250*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals/families with breast and/or ovarian cancer (PMID: 31815095 (2019), 30322717 (2018), 27767231 (2017), 26843898 (2016), 26681312 (2015), 24504028 (2014), 22009639 (2012), 20104584 (2010)), as well as various other cancer types including colon cancer, stomach cancer, and glioma (PMID: 29625052 (2018), 26689913 (2015), 26681312 (2015)). The frequency of this variant in the general population, 0.000008 (2/251234 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	Revvity Omics, Revvity	Dec 07, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Glu1250X variant has been previously observed in our lab in 2 individuals with breast and ovarian cancer. It has also been reported in the literature in 9/522 proband chromosomes of individuals with breast cancer or HBOC; although no control chromosomes were tested to establish the variant's frequency in the general population (Castilla_1994, Eng_2001, Rohlfs_1997, Swisher_2008, Thompson_2012, Tian_2000). The variant has also been identified in the UMD (n=19), BIC (n=47), Exome Server and BOCs databases. In the UMD and BIC databases, the variant was described as being causal and of important clinical significance. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897686) but no frequency information was provided therefore not very informative for assessing the population frequency. The variant leads to a premature stop codon at position 1250 which is predicted to cause premature truncation of the protein product. This is a loss of function variant and loss of function is an established disease mechanism for the BRCA1 gene. In summary, based on the above information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Castilla 1994, Ahmad 2012, Cunningham 2014, Weren 2016); Not observed at a 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 3867G>T; This variant is associated with the following publications: (PMID: 25556971, 22009639, 12497638, 8990217, 9625424, 26843898, 27534398, 9544766, 28152038, 26689913, 26681312, 28263838, 28301456, 18413725, 22469508, 27767231, 22486713, 24504028, 29446198, 30720243, 30322717, 7894491, 25525159, 32719484, 32272925) -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Glu1250*) 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 (rs28897686, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894491, 12497638, 24504028, 24728189). This variant is also known as 3867G>T. ClinVar contains an entry for this variant (Variation ID: 17672). 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	May 23, 2016	Variant summary: The BRCA1 c.3748G>T (p.Glu1250X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g.c.3904G>T/p.Glu1302X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121388 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple affected individuals and functional study showed variant with ~10% of relative HDR activity in comparison to WT BRCA1 (Lu_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 05, 2023	- -
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:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2022	The p.E1250* pathogenic mutation (also known as c.3748G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3748. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been identified in multiple individuals with hereditary breast and ovarian cancer (HBOC) syndrome (Castilla L et al. Nat. Genet. 1994 Dec;8:387-91; Valarmathi MT et al. Hum Mutat, 2003 Jan;21:98-9; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Shirts BH et al. Genet Med, 2016 10;18:974-81; Weren RD et al. Hum. Mutat. 2017 Feb;38:226-235; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Lecarpentier J et al. Breast Cancer Res, 2012 Jul;14:R99). Of note, this alteration is also designated as 3867G>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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This variant changes 1 nucleotide in exon 10 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 observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 7894491, 12497638, 18413725, 20104584, 21120943, 22469508, 22486713, 24504028, 26681312, 26845104, 27062684, 27767231; DOI: 10.21203/rs.3.rs-591403/v1, 10.21203/rs.3.rs-122156/v1) and also colon and stomach cancer and low-grade glioma (PMID: 26689913, 26681312). This variant has been identified in 80 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/) and in a breast cancer case-control meta-analysis in 4/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001240). This variant has been identified in 2/251234 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	curation	Sema4, Sema4	Sep 16, 2021	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 11, 2017

- -

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	0.28
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A;A;A;A;A;A;N;N;N;N;N;N;N;N
Vest4		0.83
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs28897686; hg19: chr17-41243800; COSMIC: COSV99066375; COSMIC: COSV99066375;