rs1555576959

Positions:

• chr17-43057116-CCT-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.5211_5212del​(p.Gly1738ArgfsTer91) 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. R1737R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.68

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43057116-CCT-C is Pathogenic according to our data. Variant chr17-43057116-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 531396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43057116-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43057116-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5211_5212del	p.Gly1738ArgfsTer91	frameshift_variant	19/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5211_5212del	p.Gly1738ArgfsTer91	frameshift_variant	19/23	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2017

This deletion of two nucleotides in BRCA1 is denoted c.5211_5212delAG at the cDNA level and p.Gly1738ArgfsX91 (G1738RfsX91) at the protein level. This variant would be defined as BRCA1 5330delAG or 5330_5331delAG using alternate nomenclature. The normal sequence, with the bases that are deleted in brackets, is TCAG[delAG]GAGA. The deletion causes a frameshift which changes a Glycine to an Arginine at codon 1738, and creates a premature stop codon at position 91 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.5211_5212delAG has been observed in at least one individual with breast cancer (Ng 2016). We consider this variant to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2017

For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg1835*) that lies downstream of this variant has been determined to be pathogenic (PMID: 12393792, 11739404, 27553291, 8554067, 10486320). This suggests that deletion of this region of the BRCA1 protein is causative of disease. This variant has been reported in an individual affected with breast cancer (PMID: 26757417). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Gly1738Argfs*91). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acids of the 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: rs1555576959; hg19: chr17-41209133;