rs80359888

chr17-43071092-CAACTTTCAATTGGGG-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_007294.4(BRCA1):c.4807_4821del(p.Pro1603_Val1607del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P1603P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 2.46

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 2 ACMG points.

• 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.4807_4821del	p.Pro1603_Val1607del	inframe_deletion	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4807_4821del	p.Pro1603_Val1607del	inframe_deletion	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251400 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461866 Hom.: 0 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 18, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 13, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 30, 1999	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2023	In-frame deletion of 5 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Also known as 4926_4940del; This variant is associated with the following publications: (PMID: 26295337, 10923033, 16280041, 27375968, 10220405, 9974970, 11301010, 37628606, 34413315) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	The BRCA1 c.4807_4821del; p.Pro1603_Val1607del variant (rs80359888), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 37611). This variant is found in the Latino population with an overall allele frequency of 0.04% (13/34592 alleles) in the Genome Aggregation Database. This variant deletes five amino acids, leaving the rest of the protein in-frame. However, given the lack of clinical and functional data, the significance of the p.Pro1603_Val1607del variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 30, 2022	The frequency of this variant in the general population, 0.00038 (13/34592 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with angiosarcoma (PMID: 32552130 (2021)) and individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 34413315 (2021)). Additionally, the variant is predicted to disrupt an exonic splicing element by an in-silico model (PMID: 16280041 (2005)). Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 22, 2023	This variant causes an in-frame deletion of 5 amino acids of the BRCA1 protein. This variant is also known as 4915del15, LKVPQ1600del and 4926_4940del15. To our knowledge, functional studies have not been performed for this variant. This variant has been detected in at least five individuals affected with breast, ovarian cancer or angiosarcoma (PMID: 16280041, 32552130; BIC database accession number 4413; Color internal data) and in an individual affected with ovarian cancer who also has a pathogenic BRCA2 covariant (ClinVar RCV000048661.8). This variant has also been identified in 13/251400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2023	The c.4807_4821del15 variant (also known as p.P1603_V1607del) is located in coding exon 14 of the BRCA1 gene. This variant results from an in-frame deletion of 15 nucleotides (CCCCAATTGAAAGTT) at nucleotide positions 4807 to 4821. This results in the deletion of five amino acid residues at codons 1603 to 1607. The deleted amino acid positions are not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 23, 2023

Variant summary: BRCA1 c.4807_4821del15 (p.Pro1603_Val1607del) results in an in-frame deletion that is predicted to remove five amino acids from the encoded protein. The variant allele was found at a frequency of 5.2e-05 in 251400 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.4807_4821del15 has been reported in the literature in individuals at risk for Hereditary Breast and Ovarian Cancer syndrome (e.g. Kang_2016, Herzog_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with an unspecified BRCA2 pathogenic variant has been reported by a ClinVar submitter (SCV000076674.8). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16280041, 34413315, 27375968). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This variant, c.4807_4821del, results in the deletion of 5 amino acid(s) of the BRCA1 protein (p.Pro1603_Val1607del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507238, gnomAD 0.04%). This variant has been observed in individual(s) with BRCA1-related conditions (PMID: 34413315). ClinVar contains an entry for this variant (Variation ID: 37611). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs80359888; hg19: chr17-41223109;