rs80358331

Positions:

• chr17-43093045-AAGC-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BP6

The NM_007294.4(BRCA1):​c.2483_2485del​(p.Gly828_Phe829delinsVal) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: -0.147

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.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-43093045-AAGC-A is Benign according to our data. Variant chr17-43093045-AAGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54582.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2483_2485del	p.Gly828_Phe829delinsVal	inframe_deletion	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2483_2485del	p.Gly828_Phe829delinsVal	inframe_deletion	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250982 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135652

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461630 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 17, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2023	The c.2483_2485delGCT variant (also known as p.G828_F829delinsV) is located in coding exon 9 of the BRCA1 gene. This variant results from an in-frame deletion of GCT at nucleotide positions 2483 to 2485. This results in the deletion of the glycine residue at codon 828 and the phenylalanine residue at codon 829 and the insertion of a valine residue. This alteration was previously identified in 1/1398 unilateral breast cancer cases and 0/705 bilateral breast cancer cases in a population based study (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). It has also been reported in a series of over 50000 patients undergoing BRCA1 sequencing (Judkins T et al. Cancer Res. 2005 Nov;65:10096-103). This amino acid region is not 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2018	Variant summary: BRCA1 c.2483_2485delGCT (p.Gly828_Phe829delinsVal) results in an in-frame deletion that is predicted to remove 2 amino acids from the encoded protein and add one. The variant allele was found at a frequency of 7.2e-06 in 276710 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2483_2485delGCT has been reported in affected individuals in the literature, without strong evidence for causality (Borg_2010, Judkins_2005). BIC (Breast Cancer Information Core) database cites the variant in an individual who carries a common pathogenic variant in BRCA1 (c.181T>G, p.Cys61Gly), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2022	The BRCA1 c.2483_2485delGCT; p.Gly828_Phe829delinsVal variant (rs80358331) is reported in the literature in an individual affected with breast cancer, but without clear disease association (Borg 2010). This variant is also reported in ClinVar (Variation ID: 54582), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes 3 nucleotides, which would replace a glycine and phenylalanine with valine, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. PMID: 20104584. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 2 amino acids and insertion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Also known as 2602_2604delGCT; This variant is associated with the following publications: (PMID: 20104584, 16267036) -

BRCA1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 01, 2024

The BRCA1 c.2483_2485delGCT variant is predicted to result in an in-frame deletion (p.Gly828_Phe829delinsVal). This variant has been reported in an individual with breast cancer (Table S2 - Borg et al. 2010. PubMed ID: 20104584) and an individual with breast and/or ovarian cancer (referred to as G828del - Judkins et al. 2005. PubMed ID: 16267036). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity of likely benign and uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/54582/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This variant, c.2483_2485del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the BRCA1 protein (p.Gly828_Phe829delinsVal). This variant is present in population databases (rs80358331, gnomAD 0.002%). This variant has been observed to co-occur in individuals with a different variant in BRCA1 that has been determined to be pathogenic (PMID: 10923033, 20104584), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 54582). 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

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: rs80358331; hg19: chr17-41245062;