rs80358333

Positions:

chr17-43092527-TTTCCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4BP6

The ENST00000357654.9(BRCA1):c.2998_3003del(p.Glu1000_Glu1001del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1000E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

BRCA1
ENST00000357654.9 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3

Conservation

PhyloP100: 1.63

Variant links:

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]

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000357654.9.

BP6

Variant 17-43092527-TTTCCTC-T is Benign according to our data. Variant chr17-43092527-TTTCCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54743.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.2998_3003del	p.Glu1000_Glu1001del	inframe_deletion	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.2998_3003del	p.Glu1000_Glu1001del	inframe_deletion	10/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250808

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461782

Hom.:

AF XY:

0.0000385

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

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:

0.0000522

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2024	In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Located in the critical DNA binding domain (PMID: 15343273); Identified in women with breast or ovarian cancer (PMID: 10359546, 11733976); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3117del6; This variant is associated with the following publications: (PMID: 10359546, 32429029, 31853058, 15343273, 31131967, 11733976) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Glu1000_Glu1001del variant has been previously reported in the BIC database as a variant of unknown clinical significance. This is an in frame-deletion which removes two amino acids (Glu-Glu) from the BRCA1 protein. The p.Glu1000 residue is conserved in mammals and the p.Glu1001 residue is not well conserved, with a Gly (glycine) at this position in mouse. However, this information does not help to predict the impact of this variant on protein function. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although this variant is of the type that may have clinical significance. Based on the above information, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	The BRCA2 c.2998_3003delGAGGAA; p.Glu1000_Glu1001del variant (rs80358333) is reported in the literature in a cohort individuals affected with early-onset breast cancer (Peto 1999). This variant is found on only five chromosomes (5/282204 alleles) in the Genome Aggregation Database. This variant deletes two moderately conserved glutamate residues, leaving the rest of the protein in-frame. However, due to limited information, the clinical significance of the p.Glu1000_Glu1001del variant is uncertain at this time. References: Peto J et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943-9. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 12, 2000	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 12, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2022	The c.2998_3003delGAGGAA variant (also known as p.E1000_E1001del) is located in coding exon 9 of the BRCA1 gene. This variant is an in-frame deletion of 6 nucleotides between nucleotide positions 2998 and 3003 and results in the deletion of 2 glutamate residues at codons 1000 and 1001. This variant was detected in breast and ovarian cancer cohorts (Gaba F et al. Cancers (Basel), 2020 May;12:); Smith SA et al. Gynecol. Oncol. 2001 Dec;83:586-92; Peto J et al. J. Natl. Cancer. Inst. 1999 Jun;91:943-9) but was classified as unknown significance in both publications. Of note, this alteration is also referred to as 3117del6 and "Glu-1000 and Glu-1001 deletion" in published literature. These amino acid positions are well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (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

Aug 22, 2024

Variant summary: BRCA1 c.2998_3003delGAGGAA (p.Glu1000_Glu1001del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2998_3003delGAGGAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Peto_1999, Smith_2001, Kang_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 10359546, 11733976, 27375968). ClinVar contains an entry for this variant (Variation ID: 54743). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over