rs80357623

chr17-43067642-AATTAG-A

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.5035_5039del(p.Leu1679TyrfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1679L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 5.60

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 17-43067642-AATTAG-A is Pathogenic according to our data. Variant chr17-43067642-AATTAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37624.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067642-AATTAG-A is described in Lovd as [Pathogenic]. Variant chr17-43067642-AATTAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5035_5039del	p.Leu1679TyrfsTer2	frameshift_variant	16/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5035_5039del	p.Leu1679TyrfsTer2	frameshift_variant	16/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 17, 2011	- -
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	Baylor Genetics	Oct 14, 2022	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	This sequence change creates a premature translational stop signal (p.Leu1679Tyrfs*2) 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 a personal and/or family history of breast and ovarian cancer (PMID: 16457150, 17591842). This variant is also known as 5154del5. ClinVar contains an entry for this variant (Variation ID: 37624). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 19, 2018	The p.Leu1679TyrfsX2 variant in BRCA1 has been reported in more than 10 individu als with hereditary breast and/or ovarian cancer (HBOC), as well as one young re portedly unaffected individual (<35 years old) with a family history of HBOC (Mu solino 2005, John 2007, Veschi 2007, Azzollini 2016, Breast Information Core (BI C): https://research.nhgri.nih.gov/bic/). This variant was absent from large pop ulation studies. The p.Leu1679TyrfsX2 variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 1679 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the BRCA1 gene is an established disease mechanism in individuals with HBOC. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (SCV000282336.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal d ominant manner based upon presence in multiple affected individuals, absence fro m the general population, and the predicted impact on the protein. ACMG/AMP Crit eria applied: PVS1, PM2, PS4_Moderate. -
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	Nov 08, 2018	Variant summary: BRCA1 c.5035_5039delCTAAT (p.Leu1679TyrfsX2) 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 (e.g. p.Glu1694X and p.Tyr1703X). The variant was absent in 246172 control chromosomes (gnomAD). c.5035_5039delCTAAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2018	This deletion of five nucleotides in BRCA1 is denoted c.5035_5039delCTAAT at the cDNA level and p.Leu1679TyrfsX2 (L1679YfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAT[delCTAAT]TACT. The deletion causes a frameshift, which changes a Leucine to a Tyrosine at codon 1679, and creates a premature stop codon at position 2 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.5035_5039delCTAAT, also published as BRCA1 5154del5 using alternate nomenclature, has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Musolino 2005, John 2007, Veschi 2007, Azzollini 2016, Pellegrino 2016). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2022	The c.5035_5039delCTAAT pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 5035 to 5039, causing a translational frameshift with a predicted alternate stop codon (p.L1679Yfs*2). Also designated as 5154del5 in some published literature, this alteration has been seen in multiple patients with breast cancer (Musolino A et al. Tumori;91(6):505-12; John EM et al. JAMA 2007 Dec;298(24):2869-76; Cruz-Correa M et al. Hered Cancer Clin Pract 2017 Jan;15:3). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 21, 2021	This variant deletes 5 nucleotides in exon 16 of the BRCA1 gene, creating a frameshift and premature translation stop signal. 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 reported in individuals and families affected with breast and ovarian cancer (PMID: 16457150, 17591842, 17592676, 18159056, 27062684). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357623; hg19: chr17-41219659;