17-43082398-A-G

Variant names:

• chr17-43082398-A-G
• rs80358143
• NM_007294.4:c.4357+6T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_007294.4(BRCA1):​c.4357+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 0.4380
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:4
• Conservation: PhyloP100: 2.21
• Publications: 7 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43082398-A-G is Pathogenic according to our data. Variant chr17-43082398-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 37585.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4357+6T>C		splice_region intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.4357+6T>C		splice_region intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.4357+6T>C		splice_region intron	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4357+6T>C		splice_region intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.4357+6T>C		splice_region intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.4357+6T>C		splice_region intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461048 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726694

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111328

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:2

Oct 06, 2006

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 02, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4357+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 11 in the BRCA1 gene. In one study, this alteration was detected in 1/32 HBOC families, a family with a history of 2 cases of breast cancer and 2 cases of ovarian cancer (Gayther SA et al. Nat Genet, 1995 Dec;11:428-33). Another study identified this variant in an individual diagnosed with ovarian cancer at age 41 who had 3 close relatives diagnosed with breast cancer under the age of 45. This same study also reported that this alteration was detected in 8/16600 families submitted for cancer testing to Public Health England and in an additional 11 affected probands in the UK DMuDB database (Smith MJ et al. Clin Genet, 2019 Apr;95:532-533). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing, however RNA studies have demonstrated that this alteration results in incomplete skipping of coding exon 11 (Smith MJ et al. Clin Genet, 2019 Apr;95:532-533; Wai HA et al. Genet Med, 2020 Jun;22:1005-1014), where 85-90% of splicing from the variant allele was estimated to be aberrant (Smith MJ et al. Clin Genet, 2019 Apr;95:532-533). In addition, internal RNA studies have also demonstrated that this alteration results in a splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.

Mar 19, 2020

Color Diagnostics, LLC DBA Color Health

Significance: 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 12 of the BRCA1 gene. Functional RNA studies have shown that this variant causes out-of-frame exclusion of exon 12, resulting in a frameshift and a premature stop codon (PMID: 7493024, 30586678). Abnormal splicing affected 85-90% of the variant allele (PMID: 30586678). This variant has been reported in multiple families affected with breast and/or ovarian cancers (PMID: 7493024, 17688236, 29337092, 30586678). 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 Pathogenic.

Hereditary breast ovarian cancer syndrome Pathogenic:1 Uncertain:1

Oct 31, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data used in classification: The variant was observed in 8 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (8/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 3e-06). At least 11 additional families have been identified in the UK (source DMuDB, these are not included in the previous dataset).There are additional reports of this variant on ClinVar. In the remainder of the GNOMAD populations (75,263 individuals), the frequency of this variant is 0. mRNA analysis of 2 patient samples and 5 controls was performed in a UK diagnostic laboratory on puromycin treated short term PHA stimulated lymphocyte cultures which showed that approx. 42.5% of the total RNA product was abnormally spliced excluding the whole of BRCA1 exon 12 resulting in disruption of the reading frame with incorporation of premature STOP codon at the start of BRAC1 exon 13. Skipping of exon13 (172 bases; out of frame) is also reported in Walker et al. Human Mutation 2013 and Gayther et al 1995 Nat Genet. PMID:7493024.. Additional data (not used in classification): Of note, insilico predictions of splicing effect for this variant were not strong (% change MaxEnt Score: -5.05, % change NNS Score: -6.95). The four UK families for whom pedigree data were available had a strong pattern of HBOC (Manchester score 20, 31, 25, 33). Additional samples from affected individual were not available for segregation analyses.

Jul 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Nucleotide substitutions within 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 12 (also called exon 13), which introduces a premature termination codon (PMID: 7493024, 30586678, 32123317). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 37585). This variant is also known as 4476+6T>C. This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 7493024, 30586678). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 12 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 disrupted protein product.

not provided Pathogenic:1

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		2.2
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.39
Splicevardb		3.0
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80358143; hg19: chr17-41234415;