17-43095845-C-T

Variant names:

• chr17-43095845-C-T
• rs398122706
• NM_007294.4:c.670+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_007294.4(BRCA1):​c.670+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.49

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43095845-C-T is Pathogenic according to our data. Variant chr17-43095845-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1755007.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.670+1G>A		splice_donor_variant, intron_variant	Intron 9 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.670+1G>A		splice_donor_variant, intron_variant	Intron 9 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460402 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726560

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 29, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.670+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the BRCA1 gene. This alteration is located at the canonical splice donor site which is skipped in one of the natural in-frame minor isoforms (known in the literature as BRCA1 delta 9-10) (Colombo M et al. Hum Mol Genet. 2014; 23:3666-80). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, in BRCA1, the pathogenicity of alterations at canonical splice sites of exons that are skipped in the naturally occurring delta 9-10 in-frame minor isoform have yet to be determined, as they may be partially functional (de la Hoya M et al. Hum. Mol. Genet. April 2016). As such, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 9 of the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 1755007). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 24569164, 27008870; Invitae). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.94
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.73	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122706; hg19: chr17-41247862; COSMIC: COSV105897789; COSMIC: COSV105897789;