17-43045700-TG-T

Position:

• chr17-43045700-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5569del​(p.Gln1857ArgfsTer65) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.41

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1863 codons.
• PP5: Variant 17-43045700-TG-T is Pathogenic according to our data. Variant chr17-43045700-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5569del	p.Gln1857ArgfsTer65	frameshift_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5569del	p.Gln1857ArgfsTer65	frameshift_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The BRCA1 c.5569delC (p.Gln1857Argfs) variant results in a frame-shift change, predicted to cause a replacement of the last 7 amino acids with 64 incorrect amino acids. Non-sense mediated mRNA decay may not happen since this variant is close the C-terminus. This alteration affects the c-terminus, including part of the BCRT domain, which is important for DNA repair activity. One in silico tool predicts a benign outcome for this variant. This variant is absent in 121000 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 10, 2022	This sequence change results in a frameshift in the BRCA1 gene (p.Gln1857Argfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the BRCA1 protein and extend the protein by 57 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with BRCA1-related disease (PMID: 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 265622). This variant disrupts the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While functional studies have not been performed to directly test the effect on BRCA1 protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2017

This deletion of one nucleotide in BRCA1 is denoted c.5569delC at the cDNA level and p.Gln1857ArgfsX65 (Q1857RfsX65) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]AGAT. Using alternate nomenclature, this variant would be defined as BRCA1 5688delC, and has not, to our knowledge, been reported in the literature. The deletion causes a frameshift which changes a Glutamine to an Arginine at codon 1857 in the last exon of the gene, and results in an extension of the protein. The last seven amino acids are replaced with 64 incorrect amino acids, disrupting a region known to interact with multiple proteins (Paul 2014). Based on currently available evidence, we consider this deletion to be a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.5569delC variant, located in coding exon 22 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5569, causing a translational frameshift, with a predicted alternate stop codon (p.Q1857Rfs*65). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 57 amino acids. This frameshift impacts the last 7 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886039675; hg19: chr17-41197717;