rs62625306

Positions:

• chr17-43093142-C-A
• chr17-43093142-C-G
• chr17-43093142-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.2389G>T​(p.Glu797*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,322 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: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: -0.0220

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]

BRCA1 (HGNC:):

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 17-43093142-C-A is Pathogenic according to our data. Variant chr17-43093142-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17682.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093142-C-A is described in Lovd as [Pathogenic]. Variant chr17-43093142-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.2389G>T	p.Glu797*	stop_gained	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2389G>T	p.Glu797*	stop_gained	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250564 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135422

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461322 Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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, 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	Counsyl	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
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	Baylor Genetics	Feb 10, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 03, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	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 identified in 1/250564 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	Ambry Genetics	May 14, 2021	The p.E797* pathogenic mutation (also known as c.2389G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2389. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in numerous individuals with breast and/or ovarian cancer (Yang D et al. JAMA. 2011 Oct;306:1557-65: Walker LC et al. Eur J Hum Genet. 2017 04;25:432-438; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). A Scottish woman diagnosed with breast cancer at age 35 was found to carry this mutation as well as a BRCA2 frameshift mutation (Liede A et al. Am. J. Hum. Genet. 1998 Jun;62(6):1543-4). 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. -

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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17682). This variant is also known as G2508T. This premature translational stop signal has been observed in individual(s) with breast cancer or ovarian cancer (PMID: 9585617, 21990299, 26681312, 27836010, 28831036). This sequence change creates a premature translational stop signal (p.Glu797*) 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). -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Glu797X variant was identified in a Canadian individual of Scottish descent diagnosed with breast cancer at age 35, who also carried a pathogenic BRCA2 mutation (c.3068dupA, alias BIC 3295insA), making her the first double (compound) heterozygote outside of the Ashkenazi Jewish population (Liede1998, Rebbeck 2016). The variant was also identified as a somatic mutation in a study looking at 429 ovarian cancer cases (frequency of 0.0023) and was not seen in 557 Causcasian controls (Kanchi 2014). The variant has also been identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs rs62625306) as “With Pathogenic, Uncertain significance allele” but no frequency information was provided, Clinvitae database (classification pathogenic), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic), the ClinVar database (classification pathogenic, reviewed by an expert panel, submitters: ENIGMA, CIMBA, GeneDx, Ambry Genetics, OMIM, SCRP, and BIC, classification not provided by Invitae), GeneInsight COGR database (classification pathogenic, by 4 clinical laboratories), the BIC database (unavailable), and UMD (3x with a ”unclassified variant” classification).The p.Glu797X variant leads to a premature stop codon at position 797, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. REFERENCES: Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, Zhang Q, Koboldt DC, Xie M, Kandoth C, McMichael JF, Wyczalkowski MA, Larson DE, Schmidt HK, Miller CA, Fulton RS, Spellman PT, Mardis ER, Druley TE, Graubert TA, Goodfellow PJ, Raphael BJ, Wilson RK, Ding L. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156. doi: 10.1038/ncomms4156. PubMed PMID: 24448499; PubMed Central PMCID: PMC4025965. Liede A, Rehal P, Vesprini D, Jack E, Abrahamson J, Narod SA. A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2. Am J Hum Genet. 1998 Jun;62(6):1543-4. PubMed PMID: 9585617; PubMed Central PMCID: PMC1377168. Rebbeck TR, Friebel TM, Mitra N, Wan F, Chen S, Andrulis IL, Apostolou P, Arnold N, Arun BK, Barrowdale D, Benitez J, Berger R, Berthet P, Borg A, Buys SS, Caldes T, Carter J, Chiquette J, Claes KB, Couch FJ, Cybulski C, Daly MB, de la Hoya M, Diez O, Domchek SM, Nathanson KL, Durda K, Ellis S; EMBRACE., Evans DG, Foretova L, Friedman E, Frost D, Ganz PA, Garber J, Glendon G, Godwin AK, Greene MH, Gronwald J, Hahnen E, Hallberg E, Hamann U, Hansen TV; HEBON., Imyanitov EN, Isaacs C, Jakubowska A, Janavicius R, Jaworska-Bieniek K, John EM, Karlan BY, Kaufman B, Investigators K, Kwong A, Laitman Y, Lasset C, Lazaro C, Lester J, Loman N, Lubinski J, Manoukian S, Mitchell G, Montagna M, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Offit K, Olah E, Olopade OI, Park SK, Piedmonte M, Radice P, Rappaport-Fuerhauser C, Rookus MA, Seynaeve C, Simard J, Singer CF, Soucy P, Southey M, Stoppa-Lyonnet D, Sukiennicki G, Szabo CI, Tancredi M, Teixeira MR, Teo SH, Terry MB, Thomassen M, Tihomirova L, Tischkowitz M, Toland AE, Toloczko-Grabarek A, Tung N, van Rensburg EJ, Villano D, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Zidan J, Zorn KK, McGuffog L, Easton D, Chenevix-Trench G, Antoniou AC, Ramus SJ. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res. 2016 Nov 11;18(1):112. PubMed PMID: 27836010; PubMed Central PMCID: PMC5106833. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2015	This pathogenic variant is denoted BRCA1 c.2389G>T at the cDNA level and p.Glu797Ter (E797X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as 2508G>T using alternative nomenclature, has been reported in association with familial breast cancer and ovarian cancer (Liede 1998, Yang 2011) and is considered pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.35	N
Vest4		0.78
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs62625306; hg19: chr17-41245159;