rs273900724

Positions:

• chr17-43090921-GCACACACACACACGCTTTTTA-GT

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.4185+2_4185+22delinsA variant causes a splice donor, splice donor 5th base, intron 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 (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 2.15

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 37, new splice context is: gtaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43090922-CACACACACACACGCTTTTTA-T is Pathogenic according to our data. Variant chr17-43090922-CACACACACACACGCTTTTTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 37574.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.4185+2_4185+22delinsA		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4185+2_4185+22delinsA		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 07, 2012	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999914 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 24, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
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 13, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 30, 2023	This sequence change affects a splice site in intron 11 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 12938098). This variant is also known as IVS12+2insAdel21. Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Studies have shown that disruption of this splice site results in retention of intron 11 and introduces a premature termination codon (PMID: 12938098). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2019	Variant summary: BRCA1 c.4185+2_4185+22delinsA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Meyer_2003). The variant was absent in 250278 control chromosomes (gnomAD). c.4185+2_4185+22delinsA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Meyer_2003, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submission (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2022	The c.4185+2_4185+22delinsA intronic pathogenic mutation, located in intron 10 of the BRCA1 gene, results from an in-frame from the deletion of 21 nucleotides and the insertion of one nucleotide at nucleotide position 4185. Of note, this alteration is also designated as IVS12+2del21insA in the literature. This alteration was classified as pathogenic in multifactorial models of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578; Easton DF et al. Am J Hum Genet, 2007 Nov;81:873-83). RNA studies have demonstrated that this alteration results in abnormal splicing (Ambry internal data; Meyer P et al. Hum Mutat, 2003 Sep;22:259). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 13, 2020	This variant alters 21 bases in intron 11 of the BRCA1 gene, abolishing the intron 11 splice donor site. This variant is also known as IVS12+2del21insA. Functional RNA studies have shown that this variant causes the retention of intron 11, resulting in premature truncation and is expected to result in an absent or non-functional protein product (PMID: 12938098). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a hereditary breast cancer family (PMID: 12938098). A multifactorial analysis reported that this variant has odds in favor of causality of 36:1 based on family history, co-occurrence and co-segregation (PMID: 17924331). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2023

Canonical splice site variant demonstrated to result in a null allele in a gene for which loss of function is a known mechanism of disease (Meyer et al., 2003); Observed in an individual with a personal and family history of breast cancer (Meyer et al., 2003); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4304+2_4304+22delinsA or IVS12+2_IVS12+22delinsA; This variant is associated with the following publications: (PMID: 17924331, 29446198, 31131967, 26295337, 12938098) -

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: rs273900724; hg19: chr17-41242939;