17-43047642-C-T

Variant names:

• chr17-43047642-C-T
• rs80358145
• NM_007294.4:c.5467+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5467+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000124 in 1,614,080 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 4.11

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of 5, new splice context is: aagGTgcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43047642-C-T is Pathogenic according to our data. Variant chr17-43047642-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43047642-C-T is described in Lovd as [Pathogenic]. Variant chr17-43047642-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5467+1G>A		splice_donor_variant, intron_variant	Intron 22 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5467+1G>A		splice_donor_variant, intron_variant	Intron 22 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6 Other:1

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 03, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 31, 2023

Baylor Genetics

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

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

not provided Pathogenic:2

Oct 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in skipping of exon 22, resulting in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease (PMID: 11428389, 24667779); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 30209399); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5586+1G>A; This variant is associated with the following publications: (PMID: 21913181, 25724305, 11428389, 24667779, 26287763, 26852015, 25085752, 25428789, 28205045, 25863477, 26250392, 26187060, 29470806, 29310832, 30702160, 30720863, 29446198, 31174498, 30093976, 33151324, 25525159, 31825140, 32427313, 30787465, 34645131, 32164585, 36463295, 30209399) -

Nov 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5467+1G>A variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 32164585 (2020), breast cancer (PMID: 31174498 (2019), 30720863 (2019), 30350268 (2018), 30093976 (2018)), and breast and/or ovarian cancer (PMID: 30702160 (2019)). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 24667779 (2014), 11428389 (2001)). One study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 12, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5467+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 21 of the BRCA1 gene. This alteration was reported in a cohort of African American high risk breast cancer patients (Churpek JE, et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9) and has been classified as pathogenic by a personal and family history weighing algorithm (Pruss D et al. Breast Cancer Res. Treat. 2014 Aug;147:119-32). Another study reported this alteration in 1/478 high risk breast cancer patients (Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150). RNA assays have demonstrated that this alteration results in exon skipping of coding exon 21 (Ambry internal data; Laskie Ostrow K et al. Cancer Genet. Cytogenet. 2001 Jun;127:188-90; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM. et al. Nature 2018 10;562(7726):217-222). Of note, this alteration is also designated as IVS23 +1G>A in published literature. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. -

Apr 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 22 of the BRCA1 gene. RNA studies have shown that this variant causes the out-of-frame skipping of exon 21, resulting in a premature truncation in carrier RNA and minigene splicing assay (PMID: 11428389, 25428789). A functional study reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in over 10 individuals and families affected with breast and ovarian cancer and 2 unaffected individuals (PMID: 11428389, 18159056, 19491284, 21913181, 25428789, 25863477, 28205045, 30093976, 30287823, 33471991, 34657357, 35671604; Color internal data) and pancreatic cancer (PMID: 36463295). An analysis of the health history of 54 carriers reported that this variant has a pathogenic impact (PMID: 25085752). 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:2

Feb 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5467+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site, and two predict the variant creates/strengthens an existing cryptic 5' splice donor site 5nt into intron 22. Experimental evidence has confirmed that this variant affects mRNA splicing, resulting in the skipping of exon 23 (Laskie_2001, Steffensen_2014). At least one publication reports experimental evidence evaluating an impact on protein function (Findlay_2018) and the variant effect resulted in <10% of normal activity. The variant allele was found at a frequency of 6.6e-06 in 150970 control chromosomes (gnomAD v3.1.2). c.5467+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Laskie_2001, Litton_2012, Judkins_2005, John_2007, Haffty_2009, Kang_2015, Mannan_2016, Chan_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 22 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with breast and ovarian cancer (PMID: 11428389, 19491284, 21913181, 25428789). This variant is also known as This variant is also known as IVS23+1G>A in the literature.. ClinVar contains an entry for this variant (Variation ID: 37673). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 22 and introduces a new termination codon (PMID: 11428389, 24667779). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 20104584, 21922593, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.89	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -4
DS_DL_spliceai		0.95		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: rs80358145; hg19: chr17-41199659;