17-43045763-TCTCGGGTCACC-TT

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.5496_5506delinsA(p.Val1833SerfsTer7) 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. V1832V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 4.98

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 91 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43045764-CTCGGGTCACC-T is Pathogenic according to our data. Variant chr17-43045764-CTCGGGTCACC-T is described in ClinVar as [Pathogenic]. Clinvar id is 55597.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5496_5506delinsA	p.Val1833SerfsTer7	frameshift_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5496_5506delinsA	p.Val1833SerfsTer7	frameshift_variant	23/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

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

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)	Dec 15, 2017	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2017	This combined deletion and insertion is denoted BRCA1 c.5496_5506del11insA at the cDNA level and p.Val1833SerfsX7 (V1833SfsX7) at the protein level. The surrounding sequence is CTGT[del11][insA]AGTG. The variant causes a frameshift, which changes a Valine to a Serine at codon 1833, and creates a premature stop codon at position 7 of the new reading frame. Due to the position of the variant, nonsense mediated decay is not expected to occur, but the variant might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene includes a portion of the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). BRCA1 c.5496_5506del11insA has been observed in multiple breast and/or ovarian cancer families and has been reported as a possible Korean founder variant (Ahn 2007, Seong 2009, Han 2011, Jang 2012, Kim 2012, Kim 2017). Based on currently available information, we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2022	The c.5496_5506del11insA pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from the deletion of 11 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.V1833Sfs*7). This alteration occurs at the 3' terminus of BRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 31 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been reported in numerous HBOC individuals, notably among the Korean population (Kim SI et al. Cancer Res Treat, 2022 Jul; Ficarazzi F et al. Breast, 2021 Aug;58:121-129; Kim SI et al. Cancer Res Treat, 2020 Oct;52:1229-1241; Yi EJ et al. Ann Thorac Surg, 2013 Aug;96:677-80; Kang E et al. J Breast Cancer, 2013 Sep;16:245-53; Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Ahn SH et al. Cancer Lett, 2007 Jan;245:90-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2021	This variant alters 11 nucleotides in exon 23 in the BRCA1 gene, causing a frameshift and disruption to the BRCT domain that is important for phosphopeptide binding and DNA damage response (PMID: 25701377). This variant has been observed in at least 15 individuals and families affected with breast and ovarian cancer (PMID: 16455195, 22798144) and an individual affected with melanoma (PMID: 23910109). This is a suspected founder mutation in Asia with many case reports from Korea (PMID: 21497495, 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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: rs273902775; hg19: chr17-41197781;