17-43093316-TA-TAA

Position:

• chr17-43093316-TA-TAA

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.2214_2215insT​(p.Lys739Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V738V) has been classified as Likely benign. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 0.0210

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 17-43093316-T-TA is Pathogenic according to our data. Variant chr17-43093316-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 186881.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2214_2215insT	p.Lys739Ter	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2214_2215insT	p.Lys739Ter	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461466 Hom.: 0 Cov.: 43 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed frameshift c.2214dup(p.Lys739Ter) variant in BRCA1 gene has been reported previously in heterozygous state in individual(s) affected with breast and/or ovarian cancer (Mannan et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant is predicted to cause loss of normal protein function through protein truncation. This sequence change creates a premature translational stop signal (p.Lys739*) 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 et al., 2010). For these reasons, this variant has been classified as Pathogenic. -
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	Baylor Genetics	Dec 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics, Rajiv Gandhi Cancer Institute & Research Center	Dec 13, 2017	Insertion of T introduces a new stop codon in exon 10 leading to a nonsense pathogenic alteration. -
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:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2021	Variant summary: BRCA1 c.2214dupT (p.Lys739X) 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. The variant was absent in 250926 control chromosomes (gnomAD). c.2214dupT has been reported in the literature in individuals affected breast and Ovarian Cancer (example: Mehta_2018, Rebbeck_2018, Judkins_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in patients with breast and/or ovarian cancer (PMID: 26911350, 30555256). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.2214dup (p.Lys739Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2021	The p.Lys739X variant in BRCA1 has been reported in at least 5 individuals with BRCA1-associated cancers (Mannan 2016 PMID: 26911350, Maistro 2016 PMID: 27914478, Mehta 2018 PMID: 30555256, Singh 2018 PMID: 29470806). It was absent from large population studies. This variant is a duplication of one base (c.2214dupT) that results in a nonsense variant and leads to a premature termination codon at position 739, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Moreover, this variant was classified as pathogenic on September 8th, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 186881). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Mar 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2023	ClinVar contains an entry for this variant (Variation ID: 186881). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26911350, 27914478). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys739*) 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:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2333dup and c.2214_2215insT; This variant is associated with the following publications: (PMID: 26911350, 16267036, 27914478, 27848044, 30555256, 29470806, 34601666, 20104584, 29446198, 35698740) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 14, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 21, 2022	The c.2214dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 2214, causing a translational frameshift with a predicted alternate stop codon (p.K739*). This mutation has been reported in two Indian hereditary breast and/ovarian cancer cohorts (Mannan A et al. J. Hum. Genet. 2016 Jun;61(6):515-22; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Aug 17, 2023	This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.2214_2215insT in the literature. 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 detected in at least 5 individuals affected with breast and/or ovarian cancer (PMID: 26911350, 30555256). This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

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: rs80357574; hg19: chr17-41245333;