17-43063399-T-C

Variant names:

• chr17-43063399-T-C
• rs80358109
• NM_007294.4:c.5153-26A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_007294.4(BRCA1):​c.5153-26A>G variant causes a intron change. The variant allele was found at a frequency of 0.00000555 in 1,441,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 B:2
• Conservation: PhyloP100: 4.80
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5153-26A>G		intron_variant	Intron 17 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5153-26A>G		intron_variant	Intron 17 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000555 AC: 8 AN: 1441940 Hom.: 0 Cov.: 28 AF XY: 0.00000557 AC XY: 4 AN XY: 718686

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33052

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52508

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1094702

Other (OTH) AF: 0.0000167 AC: 1 AN: 59782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000785262), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 15, 2001

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 18, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PM2(Supporting)+PP3(Supporting)+BS3(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary breast ovarian cancer syndrome Uncertain:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 17 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 16544996, 31228304, 34981296). ClinVar contains an entry for this variant (Variation ID: 125786). Studies have shown that this variant results in skipping of exon 18, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 32123317; internal data). 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. -

Feb 17, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data included in classification: Case control comparison of UK familial cases against ethnically matched population data (7/25,773 in familial UK cases against 0/23,509 NFE controls from GnomAD genome sequencing and UK 100,000 genome project pexact= 0.016) (PS4_strong). 1/8 segregation in one large UK family (PP1_sup). UK Family 1: Homozygous Iranian case (from consanguineous family) with normal phenotype in adulthood (age 34), no cancer and normal chromosome breakage in lymphocytes. Additional studies inc. RNA and skin biopsy were sought from this patient could not be attained. (BS2_strong). Absent from the remainder of the GnomAD population (PM2_sup). Additional data (not included in classification): In silico analysis supports aberration of splicing compared to WT due to experimentally-proven intronic branch site. Functional evidence conflicting: Mini-gene assay: suggestive of incomplete skipping of exon 19. Published RNA analyses: estimated that transcripts lacking exon 19 (41bp) account for 30-40% of all BRCA1 transcripts in blood, inferring that 10-20% of transcripts expressed from the variant allele are of full length. See also: Steffensen et al Eur J Hum Genet 2014, Rosenthal ET et al, Clin Genet 2015, Mercer, Genome Res 2015. Patient-derived RNA assay from UK diagnostic labs demonstrated the variant to cause out of frame deletion of exon 19. This results in a PTC in exon 20. Estimation that transcripts lacking exon 19 account for 30-40% of all BRCA1 transcripts in blood. Haploid yeast saturation genome editing assay shown to be functional (Findlay et al, 2018). -

Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1

Feb 09, 2024

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: BS3, PP3, PS1_MOD, PM2_SUP -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 07, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5153-26A>G intronic variant results from an A to G substitution 26 nucleotides upstream from coding exon 17 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration is at a branch point which is a pre-mRNA feature that is important for correct splicing (Leman R et al. BMC Genomics, 2020 Jan;21:86; Canson D et al. Hum. Mutat., 2020 Jul). This alteration has been identified in several patients with breast and/or ovarian cancer (Bisgin A et al. Breast J., 2019 09;25:1029-1033; Tabarestani S et al. Int. J. Cancer Manag., 2017 10(12):e60392; CanVig Data-ClinVar). This variant has also been identified in the homozygous state in an adult with normal chromosome breakage studies (Personal communication). In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in a substantial but incomplete splice defect; however the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data; CanVIG Data-ClinVar, Personal communication; Wai HA et al. Genet. Med., 2020 Jun;22:1005-1014; Leman R et al. BMC Genomics, 2020 Jan;21:86). This nucleotide substitution is functional in a high throughput genome editing haploid cell survival assay that can measure both protein and RNA effects (Findlay GM et al. Nature, 2018 10;562:217-222). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.59
PhyloP100		4.8
La Branchor		0.74
BranchPoint Hunter		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -26

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

Other links and lift over

dbSNP: rs80358109; hg19: chr17-41215416;