rs80358345

chr17-43063945-TCAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_007294.4(BRCA1):c.5078_5080del(p.Ala1693del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1693A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:2
• Conservation: PhyloP100: 3.32

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 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_007294.4
• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-43063945-TCAG-T is Pathogenic according to our data. Variant chr17-43063945-TCAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063945-TCAG-T is described in Lovd as [Pathogenic]. Variant chr17-43063945-TCAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5078_5080del	p.Ala1693del	inframe_deletion	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5078_5080del	p.Ala1693del	inframe_deletion	17/23	1	NM_007294.4	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/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 30, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 12, 2000	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2016

This in-frame deletion of 3 nucleotides in BRCA1 is denoted c.5078_5080delCTG at the cDNA level and p.Ala1693del (A1693del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 c.5197_5199delCTG. The normal sequence, with the bases that are deleted in braces, is GATG[CTG]AGTT. This deletion of a single Alanine residue occurs at a position that is not conserved across species and is located in the BRCT 1 domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). This variant was observed in a breast/ovarian cancer family and was shown in splicing assays to result in skipping of exon 18 in both cDNA and RNA (Díez 2003, Houdayer 2012, Campos 2003). We consider this deletion to be likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2023

The c.5078_5080delCTG variant (also known as p.A1693del) is located in coding exon 16 of the BRCA1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 5078 to 5080. This results in the in-frame deletion of an alanine at codon 1693. This alteration (also designated as c.5196del3 and c.5197_5199del3 in the literature) has been identified in Spanish breast and ovarian cancer cohorts (Diez, O et al. Hum Mutat. 2003 Oct;22(4):301-12; Pajares B et al. BMC Cancer 2018 Jun;18(1):647). This alteration was deleterious in a transcriptional activation assay (Nepomuceno TC et al. Sci Rep 2022 Sep;12(1):16203). RNA studies have shown this variant to result in the in-frame deletion of coding exon 16 (Campos, B et al. Hum Mutat. 2003 Oct;22(4):337; Houdayer, C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55386). This variant is also known as 5197_5199del3. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12955716, 29446198, 29884136). This variant is not present in population databases (gnomAD no frequency). This variant, c.5078_5080del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.Ala1693del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs80358345; hg19: chr17-41215962;