rs80357721

chr17-43045748-CT-C

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.5521del(p.Ser1841ValfsTer2) 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. S1841S) 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:5
• Conservation: PhyloP100: 4.25

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 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 46 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43045748-CT-C is Pathogenic according to our data. Variant chr17-43045748-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55612.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045748-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43045748-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5521del	p.Ser1841ValfsTer2	frameshift_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5521del	p.Ser1841ValfsTer2	frameshift_variant	23/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

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)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 06, 1999	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.5521delA pathogenic mutation, located in coding exon 22 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5521, causing a translational frameshift with a predicted alternate stop codon (p.S1841Vfs*2). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 22 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 alteration was detected in a cohort of women diagnosed with breast cancer (Malone KE, JAMA 1998 Mar;279(12):922-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 13, 2018

For these reasons, this variant has been classified as Pathogenic. This truncation is expected to partially remove the C-terminal BRCT domain of BRCA1 protein, which is important for DNA repair activity (PMID: 14576433, 15133503). A different deleterious variant p.Tyr1853* located downstream of this variant has been shown to disrupt BRCA1 protein function (PMID: 8942979, 20681793, 10811118, 11256609, 17308087), suggesting that although this particular variant may not result in nonsense mediated decay, it is expected to affect BRCA1 protein function. This variant has been reported in individuals affected with breast cancer (PMID: 9544766, 16835750, 21614564, 27393621). This variant is also known as 5640delA in the literature. ClinVar contains an entry for this variant (Variation ID: 55612). This variant is not present in population databases (ExAC no frequency). This sequence change deletes 1 nucleotide in exon 23 of the BRCA1 mRNA (c.5521delA), causing a frameshift at codon 1841. This creates a premature translational stop signal in the last exon of the BRCA1 mRNA (p.Ser1841Valfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated protein by eliminating 22 amino acid residues from the full-length BRCA1 protein. -

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: rs80357721; hg19: chr17-41197765;