rs80357564

chr17-43091820-TA-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.3710del(p.Ile1237AsnfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: -0.384

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 17-43091820-TA-T is Pathogenic according to our data. Variant chr17-43091820-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 54972.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091820-TA-T is described in Lovd as [Pathogenic]. Variant chr17-43091820-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3710del	p.Ile1237AsnfsTer27	frameshift_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3710del	p.Ile1237AsnfsTer27	frameshift_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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:7

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 17, 2010	- -
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	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 14, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Ile1237AsnfsX27 variant in BRCA1 has been reported in >65 individuals with BRCA1-related cancers (first published by Johannsson, 1996 PMID: 8644702). It was absent from large population studies. This variant was classified as Pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 54972). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1237 and leads to a premature termination codon 27 amino acids downstream. This alteration is then 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). Another variant additional variants involving this codon (c.3710_3711delTA, p.Ile1237Thrfs*6) has been identified in individuals with HBOC and is classified as pathogenic by other laboratories. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -
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	Invitae	Dec 08, 2023	This sequence change creates a premature translational stop signal (p.Ile1237Asnfs*27) 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 variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is also known as 3829delT. ClinVar contains an entry for this variant (Variation ID: 54972). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2018	Variant summary: BRCA1 c.3710delT (p.Ile1237AsnfsX27) 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 (eg. p.Glu1250X, p.Ser1253fsX10, p.Lys1254X). The variant was absent in 246022 control chromosomes (gnomAD). c.3710delT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Kurian_2008, Malander_2003, Thomassen_2008). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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	GeneDx	Sep 21, 2017	This deletion of one nucleotide in BRCA1 is denoted c.3710delT at the cDNA level and p.Ile1237AsnfsX27 (I1237NfsX27) at the protein level. The normal sequence, with the base that is deleted in brackets, is AATA[delT]ACCT. The deletion causes a frameshift which changes an Isoleucine to an Asparagine at codon 1237, and creates a premature stop codon at position 27 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.3710delT, also defined as BRCA1 3829delT using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer syndrome and has been reported as a recurrent variant in Scandinavian populations (Johannsson 1996, Loman 2001, Malander 2004, Thomassen 2008). We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 25, 2019	The BRCA1 c.3710delT; p.Ile1237fs variant (rs80357564), also known as 3829delT, is reported in the literature in individuals with breast and ovarian cancer syndrome (Heramb 2018, Johannsson 1996, Safra 2013). This variant is also reported as pathogenic in ClinVar (Variation ID: 54972). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Johannsson O et al. Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. Am J Hum Genet. 1996 Mar;58(3):441-50. Safra T et al. BRCA mutations and outcome in epithelial ovarian cancer (EOC): experience in ethnically diverse groups. Ann Oncol. 2013 Nov;24 Suppl 8:viii63-viii68. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2024	The c.3710delT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3710, causing a translational frameshift with a predicted alternate stop codon (p.I1237Nfs*27). This alteration has been reported in multiple patients with breast and/or ovarian cancer and has been established as a common mutation in the Scandinavian region (Johannsson O et al. Am. J. Hum. Genet., 1996 Mar;58:441-50; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93(16):1215-23; Malander S et al. Eur. J. Cancer, 2004 Feb;40:422-8; Soegaard N et al. Clin. Cancer Res. 2008 Jun;14(12):3761-7); Thomassen N et al. Acta Oncol 2008 ;47(4):772-7; Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Janaviius R. EPMA J, 2010 Sep;1:397-412; Safra T et al. Ann. Oncol., 2013 Nov;24 Suppl 8:viii63-viii68; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan 10;16:3). Of note, this alteration is also referred to as 3829delT 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 07, 2021	This variant deletes 1 nucleotide in exon 10 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 multiple individuals and families affected with breast and ovarian cancer (PMID: 8644702, 11504767, 14746861, 18465347, 18559594, 20104584, 24131973) and it has been reported as a recurrent mutation in Scandinavian populations (PMID: 10788334, 18465347, 23199084). 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)		0.010		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: rs80357564; hg19: chr17-41243837;