rs28897686

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007294.4(BRCA1):​c.3748G>T​(p.Glu1250*) 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 (★★★). 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

Scores

2
2
3

Clinical Significance

Pathogenic reviewed by expert panel P:29

Conservation

PhyloP100: 0.505
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.3748G>T p.Glu1250* stop_gained Exon 10 of 23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.3748G>T p.Glu1250* stop_gained Exon 10 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1

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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12
Aug 26, 2022
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 17, 2015
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 05, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 20, 2015
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 22, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 08, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Dec 01, 1994
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:6
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Jul 18, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 21, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Dec 07, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5
Sep 05, 2023
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 23, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Apr 20, 2017
Department of Pathology and Molecular Medicine, Queen's University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3
Feb 22, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 16, 2021
Sema4, Sema4
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Mar 22, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not specified Pathogenic:1
Jan 11, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Pathogenic:1
Jul 29, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:1
Feb 23, 2017
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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