17-43063868-A-G

Variant names:

• chr17-43063868-A-G
• rs80358074
• NM_007294.4:c.5152+6T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PVS1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5152+6T>C variant is an intronic variant occurring in intron 17(18) of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold >0.20) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 32123317, 32761968). The percent reference (full-length) and aberrant transcripts produced from the variant allele is not stated, however assessment of gel electrophoresis shows apparent (near) complete splicing effect. Final code strength determined by the rubric: PVS1_Strong (RNA). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.65 (based on Co-occurrence LR=1.07; Family History LR=0.61), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PVS1_Strong (RNA)). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003291/MONDO:0700268/092

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 0.9952
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 5.73
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5152+6T>C		splice_region_variant, 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.5152+6T>C		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456188 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724888

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106862

Other (OTH) AF: 0.0000166 AC: 1 AN: 60180

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Apr 03, 2017

Counsyl

Significance: Uncertain significance

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.

Aug 01, 2020

Kong lab, Department of Laboratory Medicine, National Cancer Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5152+6T>C variant in BRCA1 has been detected in a PT51 patient, who was diagnosed with triple-negative breast cancer (TNBC) IDC at 39 years of age. BRCA1 c.5152+6T>C mRNA transcripts were abnormal compared with their corresponding wild-type transcripts (effect on RNA splicing); this variant produced a combined exon 17 and 19 by exon 18 skipping in BRCA1 and was predicted to be an in-frame deletion (26 amino acids: 1692~1717 a.a.) of the BRCA1 C-terminal (BRCT) domain of BRCA1 (Ryu 2020; PMID: 32761968). This variant does not have frequency information in genome databases, including ExAC (http://exac.broadinstitute.org/) and gnomAD (http://gnomad.broadinstitue.org), and has not been reported in the literature. Moreover, BRCA1 c.5152+6T>C was not detected in the 393 healthy female Korean controls (Ryu 2020; PMID: 32761968). By employing a saturation-genome-editing technique based on CRISPR-mediated homology-directed repair, Findlay et al suggested that BRCA1 c.5152+6T>C is a loss-of-function variant (PMID: 30209399). Thus, BRCA1 c.5152+6T>C has been classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5152+6T>C intronic pathogenic mutation results from a T to C substitution 6 nucleotides after coding exon 16 in the BRCA1 gene. Two functional studies have found that this nucleotide substitution is deleterious (Findlay GM et al. Nature. 2018 10;562:217-222; Wai HA et al. Genet Med. 2020 06;22:1005-1014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A close match alteration at the same nucleotide position, BRCA1 c.5152+6T>G, demonstrated abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Feb 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to C nucleotide substitution at the +6 position of intron 17 of the BRCA1 gene. Multiple splicing prediction tools indicate this variant may impair RNA splicing. RNA studies have reported that this variant causes aberrant splicing and in-frame skipping of exon 17 (exon 18 based on the BIC nomenclature) (PMID: 32123317, 32761968). The aberrant transcript is expected to result in nonfunctional protein product with p.Asp1692_Trp1718delinsGly in the BRCT1 domain of the BRCA1 protein. This variant has also been reported to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). Other nucleotide substitutions at the same position, c.5152+6T>A and c.5152+6T>G, are also reported to result in loss of BRCA1 function in the same study (PMID: 30209399). This variant has been observed in an individual with triple-negative breast cancer with family history of ovarian cancer in a second-degree relative (PMID: 32761968) and in an individual with ovarian cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

BRCA1-related cancer predisposition Pathogenic:1

Aug 21, 2025

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.5152+6T>C variant is an intronic variant occurring in intron 17(18) of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold >0.20) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 32123317, 32761968). The percent reference (full-length) and aberrant transcripts produced from the variant allele is not stated, however assessment of gel electrophoresis shows apparent (near) complete splicing effect. The complete splicing effect has been confirmed in an allele-specific RT-PCR assay by an Internal lab contributor. Final code strength determined by the rubric: PVS1 (RNA). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.65 (based on Co-occurrence LR=1.07; Family History LR=0.61), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PVS1 (RNA)).

Hereditary breast ovarian cancer syndrome Pathogenic:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary breast and ovarian cancer (external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 125777). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 32123317, 32761968). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
Splicevardb		3.0
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 6

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

Other links and lift over

dbSNP: rs80358074; hg19: chr17-41215885;