rs80357260

Positions:

• chr17-43090946-G-A
• chr17-43090946-G-C
• chr17-43090946-G-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.4183C>T​(p.Gln1395*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,456,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1395Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic reviewed by expert panel P:28
• Conservation: PhyloP100: 6.15

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 17-43090946-G-A is Pathogenic according to our data. Variant chr17-43090946-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55125.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43090946-G-A is described in Lovd as [Pathogenic]. Variant chr17-43090946-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4183C>T	p.Gln1395*	stop_gained, splice_region_variant	11/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4183C>T	p.Gln1395*	stop_gained, splice_region_variant	11/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242836 Hom.: 0 AF XY: 0.00000763 AC XY: 1 AN XY: 131038

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: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456324 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723830

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12

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, 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	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 17, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 07, 2022	A heterozygous nonsense splice site proximal variation in exon 11 of the BRCA1 gene that results in a stop codon and premature truncation of the protein at codon 1395 was detected . The variant is documented as pathogenic in hereditary breast ovarian cancer syndrome in the ClinVar database. The variant has not been reported in the 1000 genomes and gnomAD databases . The in-silico prediction of the variant is damaging by Mutation Taster2 tool. The reference codon is conserved across species. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This variant has been reported in individuals and families affected with breast cancer, ovarian cancer and peritoneal carcinoma (Walsh T et al). The variant is reported with the allele frequency of 0.0004118% in gnomAD database and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln1395*) 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 (Borg A et al.). The nucleotide change in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 21, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	BRCA1: PVS1, PM2, PP1, PS4:Supporting -
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	GeneDx	Nov 10, 2020	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 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 4302C>T; This variant is associated with the following publications: (PMID: 31528241, 31090900, 30322717, 29161300, 29446198, 29907814, 30720243, 29470806, 28135048, 26911350, 26681312, 27553291, 27425403, 26986251, 16287141, 25722380, 20104584, 16683254, 24728189, 19941162, 21559243, 25452441, 17949280, 14672397, 27225819, 24504028, 23772696, 16998791, 16847550, 26014432, 8531967, 22006311) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2020	This variant causes the premature termination of BRCA1 protein synthesis. It has been reported in numerous individuals/families with hereditary breast/ovarian cancer syndrome in the published literature (PMID: 31528241 (2019), 31090900 (2019), 30322717 (2018), 29907814 (2018), 29470806 (2018), 29446198 (2018), 29161300 (2017), 27553291 (2016), 27425403 (2016), 26681312 (2015), 26014432 (2015), 24728189 (2014), 24504028 (2014), 23772696 (2014), 22006311 (2011), 16998791 (2006), 16847550 (2006), 11802209 (2002), 8531967 (1996)). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 29, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2021	Variant summary: BRCA1 c.4183C>T (p.Gln1395X) 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 allele was found at a frequency of 4.1e-06 in 245892 control chromosomes. c.4183C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, one expert panel (ENIGMA) and a consortium (CIMBA) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Gln1395*) 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 (rs80357260, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer and peritoneal carcinoma (PMID: 8531967, 22006311, 24504028, 26681312, 27553291). This variant is also known as 4302C>T. ClinVar contains an entry for this variant (Variation ID: 55125). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2024	The c.4183C>T (p.Q1395*) alteration, located in exon 11 (coding exon 10) of the BRCA1 gene, consists of a C to T substitution at nucleotide position 4183. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 1395. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/242836) total alleles studied. The highest observed frequency was 0.001% (1/109528) of European (non-Finnish) alleles. This mutation has been extensively reported in the literature in individuals with a personal and/or family history of breast and/or ovarian and/or peritoneal cancer and/or colon cancer and associated with somatic loss of heterozygosity (Langston, 1996; Walsh, 2011; Cunningham, 2014; Rashid, 2016; Alemar, 2016; Alemar, 2017; Palmero, 2018; Singh, 2018; Soyano, 2018), as well as in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck, 2018). This alteration has also been shown to be highly prevalent in the Tyrolean population of Austria (P&ouml;lsler, 2016). Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 02, 2021	This variant changes 1 nucleotide in exon 11 of the BRCA1 gene, creating a premature translation stop signal in the BRCA1 protein. 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 observed in individuals affected with breast and ovarian cancer (PMID: 8531967, 16760289, 16847550, 22711857, 24728189, 26014432, 26681312, 27553291, 29470806, 30322717, 31090900) and is reported to be a founder mutation in the Tyrolean population in Austria (PMID: 26014432). This variant has been identified in 1/242836 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:2

Pathogenic, criteria provided, single submitter	research	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	Jan 30, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Sep 25, 2013	The variant BRCA1:c.4183C>T p.(Gln1395Ter) , which is located in the coding exon 11 of the BRCA1 gene, results from a cytosine-to-thymine substitution at nucleotide position 4183. The glutamine at protein position 1395 is replaced by a premature stop codon which is predicted to cause protein truncation or absence due to non-sense mediated decay. The variant has already been extensively published in unrelated individuals with personal and fammilial history of breast cancer (PMID: 29446198, 22006311, 8531967, 30322717) and also co-segregates with the disease (PMID: 15340362, 20104584, 29907814). It is considered a Tyrolean founder mutation (PMID: 26014432). In the ClinVar database, the variant have multiple entries (25) for Pathogenic or Likely pathogenic (VCV000055125.41) and is assessed as Pathogenic by the ENIGMA expert committee. This variant is very rare in the overall population (no carriers in gnomAD, gnomAD V3.1.2). The variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Aug 09, 2013

- -

BRCA1-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

The c.4183C>T (p.Gln1395*) variant in the BRCA1 gene is located in exon 11, and is predicted to create a premature termination codon resulting in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast, ovarian and peritoneal carcinoma (PMID: 8531967, 16847550, 16998791, 22006311, 24504028, 24728189, 26014432, 26681312, 27425403, 27553291, 29161300, 29446198, 29470806, 29907814, 30322717, 31090900). This variant has been reported to be a founder mutation in the Tyrolean population (PMID: 26014432). Truncating variants in BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). This variant is rare (1/242836 chromosomes) in the general population by the Genome Aggregation Database. This variant has been classified as pathogenic by multiple submitters in ClinVar including the expert panel. Therefore the c.4183C>T (p.Gln1395*) variant of the BRCA1 gene is classified as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Gln1395X variant has been previously reported in the literature in 2 of 512 proband chromosomes from individuals with hereditary breast and ovarian cancer and absent from 100 control chromosomes (Langston 1996, Rashid 2006). In addition, this variant is reported in the BIC database 28x as clinically important and the UMD database 35x as causal. This variant leads to a premature stop codon at position 1395, which is predicted to lead to a truncated or absent protein product and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.94
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357260; hg19: chr17-41242963; COSMIC: COSV99066409; COSMIC: COSV99066409;