rs80357989

Positions:

• chr17-43094680-T-TGTAATGA

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.850_851insTCATTAC​(p.Gln284LeufsTer5) 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 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14 U:1
• Conservation: PhyloP100: 1.50

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 17-43094680-T-TGTAATGA is Pathogenic according to our data. Variant chr17-43094680-T-TGTAATGA is described in ClinVar as [Pathogenic]. Clinvar id is 55735.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.850_851insTCATTAC	p.Gln284LeufsTer5	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.850_851insTCATTAC	p.Gln284LeufsTer5	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727108

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:14 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR, PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 17, 1998	- -
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, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2016	The p.Gln284fs variant in BRCA1 has been reported in >10 Caucasian individuals with BRCA1-associated cancers (Ozcelik 2003, Stegel 2011, Krajc 2014) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 284 and leads to a premature stop codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. -
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	Aug 12, 2024	Variant summary: BRCA1 c.844_850dupTCATTAC (p.Gln284LeufsX5) 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 251110 control chromosomes. c.844_850dupTCATTAC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stegel_2011, Ozcelik_2003, Krajc_2014, van der Stoep_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21232165, 12920083, 23397983, 19370767). ClinVar contains an entry for this variant (Variation ID: 55735). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2022	This sequence change creates a premature translational stop signal (p.Gln284Leufs*5) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55735). This premature translational stop signal has been observed in individual(s) with pancreatic ductal adenocarcinoma and a personal and/or family history of breast and/or ovarian cancer (PMID: 12920083, 16287141, 22923021, 23635950, 25940717, 26306726, 28740454). This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2017	This duplication of seven nucleotides in BRCA1 is denoted c.844_850dupTCATTAC at the cDNA level and p.Gln284LeufsX5 (Q284LfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CAGC[dupTCATTAC]AGCA. The duplication causes a frameshift which changes a Glutamine to a Leucine at codon 284, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.844_850dupTCATTAC, previously published as 969ins7 using alternate nomenclature, has been reported in multiple individuals with hereditary breast and/or ovarian cancer and is described as a recurrent variant in the Slovenian population (Stegel 2011, Navokovic 2012, Dobricic 2013, Karami 2013, Cini 2016, Cvelbar 2017). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 02, 2020	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast, ovarian, and pancreatic cancers in the published literature (PMID: 30940100 (2019), 26306726 (2015), 25940717 (2015), 23635950 (2013), 12920083 (2003)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 30, 2023	This variant inserts 7 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 969ins7 and 970ins7 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 multiple individuals and families affected with breast and/or ovarian cancer (PMID: 12920083, 23635950, 26852130) including recurrent affected families in Slovenia (PMID: 22923021). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 2020	The c.844_850dupTCATTAC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TCATTAC at nucleotide position 844, causing a translational frameshift with a predicted alternate stop codon (p.Q284Lfs*5). This mutation has been reported in several high-risk breast/ovarian cancer families (Ozcelik H, J. Med. Genet. 2003 Aug; 40(8):e91; Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Dobrii J et al. J Hum Genet, 2013 Aug;58:501-7; Krajc M et al. Clin Genet, 2014 Jan;85:59-63; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Cini G et al. BMC Med Genet, 2016 Feb;17:11; Cvelbar M et al. Radiol Oncol, 2017 Jun;51:187-194; Gornjec A et al. BMC Cancer, 2019 Apr;19:296; Nguyen-Dumont T et al. Genet Res (Camb), 2020 08;102:e6) as well as in a pancreatic cancer cohort (Holter S et al. J Clin Oncol, 2015 Oct;33:3124-9). In particular, this mutation has been reported frequently in the Slovenian population (Stegel V et al. BMC Med Genet, 2011 Jan;12:9; Novakovi S et al. Int J Oncol, 2012 Nov;41:1619-27; Krajc M et al. Clin Genet, 2014 Jan;85:59-63). Of note, this alteration is also referred to as 969ins7, 970ins7 , and 850_851insTCATTAC in the 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. -

Rhabdomyosarcoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 10, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357989; hg19: chr17-41246697;