rs80357590

Positions:

• chr17-43049191-TG-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.5335del​(p.Gln1779AsnfsTer14) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 1.86

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 17-43049191-TG-T is Pathogenic according to our data. Variant chr17-43049191-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37657.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43049191-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43049191-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5335del	p.Gln1779AsnfsTer14	frameshift_variant, splice_region_variant	21/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5335del	p.Gln1779AsnfsTer14	frameshift_variant, splice_region_variant	21/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251422 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 28, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A pathogenic variant was detected in this sample .This sequence change creates a premature translational stop signal (p.Gln1800fs) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11920621, 21324516, 26187060). This variant is also known as 5398delC. ClinVar contains an entry for this variant (Variation ID: 37657). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger Sequencing. Genetics counseling is recommended -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 04, 2021	we found this variant in a 55-year-old female with unilateral breast cancer (Ductal Carcinoma). she has history of colorectal cancer in her first degree relatives (her mother). -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: The BRCA1 c.5335delC (p.Gln1779Asnfs) 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.5387C>A, p.Ser1796X; c.5417delC, p.Pro1806fs). One in silico tool predicts a damaging outcome for this variant and this variant is absent in 121004 control chromosomes. The variant has been reported in numerous patients in the literature and databases, and has been reported as a Filipino founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change creates a premature translational stop signal (p.Gln1779Asnfs*14) 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 ovarian cancer (PMID: 11920621, 21324516, 26187060). This variant is also known as 5454delC. ClinVar contains an entry for this variant (Variation ID: 37657). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2023	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in multiple individuals with breast or ovarian cancer (PMIDs: 32856862 (2020), 29937436 (2018), 28664506 (2017), 22277901 (2012), 20579331 (2012), 21324516 (2011), 11920621 (2002)). The frequency of this variant in the general population, 0.000004 (1/251422 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	GeneDx	Feb 02, 2023	Frameshift 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; Published functional studies demonstrate a significant decrease of HDR activity (Lu et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5454delC; This variant is associated with the following publications: (PMID: 30702160, 29452958, 32856862, 11920621, 25814778, 21324516, 22277901, 20579331, 28918466, 26187060, 17591843, 16267036, 28664506, 29487695, 29937436, 29128982, 29625052, 31825140, 30787465, 31892343, 20104584, 35205313, 26689913) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Gln1779AsnfsX14 variant has been reported in the literature in at least 3/1352 proband chromosomes from individuals with hereditary breast and/or ovarian cancer; although no control chromosomes were tested in these particular studies to establish its frequency in the general population (Selected publications: Kuo 2012; Matsuda 2002; Ferla 2007). Of particular interest is the finding that this variant is reported as a founder mutation in Malay and Philippine breast cancer patients (Ferla 2007), and that the ethnic background of this individual is Filipino. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1779 and leads to a premature stop codon 14 codons downstream. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast cancer patients. In summary, based on the above information, this variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.5335delC pathogenic mutation, located in coding exon 20 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5335, causing a translational frameshift with a predicted alternate stop codon (p.Q1779Nfs*14). This mutation has been reported in multiple breast and ovarian cancer patients (De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Kuo WH et al. J. Hum. Genet. 2012 Feb;57:130-8; Ibrahim SS et al. J. Exp. Clin. Cancer Res. 2010 Jun;29:82; Yang XR et al. Breast Cancer Res.Treat. 2017 Oct;165:687-697; Kwong A et al. Hong Kong Med J. 2018 06;24 Suppl 3(3):4-6). Of note, this alteration is also designated as 5454delC 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357590; hg19: chr17-41201208;