rs797045175

Positions:

• chr17-43095918-CCACA-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.594_597del​(p.Ser198ArgfsTer35) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.25

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 20 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43095918-CCACA-C is Pathogenic according to our data. Variant chr17-43095918-CCACA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43095918-CCACA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.594_597del	p.Ser198ArgfsTer35	frameshift_variant, splice_region_variant	9/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.594_597del	p.Ser198ArgfsTer35	frameshift_variant, splice_region_variant	9/23	1	NM_007294.4	ENSP00000350283	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/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Fanconi anemia, complementation group S Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Fanconi anemia complementation group A Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2019

The c.594_597delTGTG variant, located in coding exon 8 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 594 to 597, causing a translational frameshift with a predicted alternate stop codon (p.S198Rfs*35). This alteration was identified in a compound heterozygous state with another pathogenic BRCA1 alteration in a patient with features that were consistent with Fanconi Anemia including increased chromosome breakage upon DNA damage. Cells from this patient had numerous defects including reduced BRCA1 and RAD51 foci formation and ultrasensitivity to PARP inhibitors. These defects were rescued by a partial BRCA1 transgene to a level comparable to a sibling whose cells had only one BRCA1 alteration. This suggests that these defects are due specifically to BRCA1 deficiency (Sawyer SL et al. Cancer Discov, 2015 Feb;5:135-42). Alterations that result in premature protein truncation are typically deleterious in nature; however, this alteration occurs in one of the exons that is absent in a predominant, in-frame, naturally occurring isoform (Δ7_8, also known as Δ9,10 in the literature) and is likely to be spliced out in this normal isoform that produces a partially functional protein (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52), Therefore, the effect of this variant in a heterozygous state may be hypomorphic. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 0
DS_AL_spliceai		0.83		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045175; hg19: chr17-41247935;