rs1555597224

chr17-43106477-CATAAAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM4

The NM_007294.4(BRCA1):c.185_190del(p.Pro62_Cys64delinsArg) variant causes a inframe deletion change. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P62P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_007294.4
• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.185_190del	p.Pro62_Cys64delinsArg	inframe_deletion	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.185_190del	p.Pro62_Cys64delinsArg	inframe_deletion	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 03, 2017

In summary, this is a novel variant with uncertain impact on protein function. While it affects a residue that has been shown to be important for protein function, without additional genetic or functional data it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant. However, this variant affects the highly conserved Cys64 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421, 20029420). Three missense substitutions at this codon (p.Cys64Arg, p.Cys64Tyr, p.Cys64Gly) have been determined to be pathogenic (PMID: 24516540, 26246475, 11320250, 15131401, 7894491, 23867111). This suggests that the cysteine residue is critical for BRCA1 protein function and that other alterations of this residue may also be pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. This sequence change deletes 6 nucleotides from exon 4 of the BRCA1 mRNA (c.185_190delCTTTAT). This leads to the deletion of 2 amino acid residues and the insertion of one amino acid residue in the BRCA1 protein (p.Pro62_Cys64delinsArg), but otherwise preserves the integrity of the reading frame. -

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: rs1555597224; hg19: chr17-41258494;