17-43099881-C-A

Position:

chr17-43099881-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_007294.4(BRCA1):c.442-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,606,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: -0.276

Variant links:

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 links:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018776825 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 3, new splice context is: tttaccatactgtttatcAGgaa. Cryptic site results in inframe 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 17-43099881-C-A is Pathogenic according to our data. Variant chr17-43099881-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462651.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=2}. Variant chr17-43099881-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.442-1G>T		splice_acceptor_variant, intron_variant		ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.442-1G>T		splice_acceptor_variant, intron_variant		1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251404

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454248

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 12, 2018	This c.442-1G>T variant in the BRCA1 gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. This variant has an extremely low frequency in large databases of genetic variation in the general population. Loss of function variants in the BRCA1 gene have been associated with familial breast-ovarian cancer-1 (BROVCA1, MIM# 604370). Therefore, this c.442-1G>T variant in the BRCA1 gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Mar 18, 2020	The c.442-1G>T variant in the BRCA1 gene is a heterozygous canonical splice site variant, which affects an acceptor splice site in intron 6 (23 introns total; NM_007300.4). A substitution at this site is predicted to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Computational splicing tools have mixed results, where several predict the 3' acceptor site to be abolished, but also predict the strengthening of a cryptic 3' acceptor site that would only result in an in-frame deletion of several amino acids. There is some experimental data to show that the latter scenario may be true (PMID: 24569164). Currently, we do not definitively know which effect on the protein this variant will cause. This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/282,812), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this variant has not been reported in individuals affected with Hereditary Breast and Ovarian Cancer. Heterozygous loss-of-function variants in BRCA1, distal to this variant have been described to be associated with an increased risk of developing breast and ovarian cancer. However, the exact risk of breast and ovarian cancer, if any, conferred by this specific variant has not been determined. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2024	The c.442-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 6 of the BRCA1 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Canonical splice site variants are typically considered deleterious; however, alterations at this particular splice acceptor site result in a transcript with a predicted in-frame loss of a single amino acid at the beginning of coding exon 6 (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). This single amino acid loss is a naturally occurring isoform and may be referred to as Δ8p in some literature (Colombo M et al. Hum Mol Genet., 2014 Jul;23:3666-80). The functional and clinical significance of this single amino acid loss is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 29, 2024

Variant summary: BRCA1 c.442-1G>T 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. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, while three predict the variant creates or strengthens an in-frame cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The ENIGMA Consortium recommends a reduced PVS1 evidence strength (PVS1_supporting) for variants altering this splice site, as they may result in functional in-frame transcripts that could rescue gene functionality. The variant allele was found at a frequency of 4e-06 in 251404 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442-1G>T has been reported in the literature in a study of patients with breast and/or ovarian cancer without strong evidence of causality (Bhaskaran_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 462651). Six submitters have classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2022

Canonical splice site variant predicted to result in aberrant splicing, potentially leading to a known naturally occurring isoform, the in-frame deletion of a single amino acid, p.Gln148del (Colombo 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 561-1G>T and IVS7-1G>T; This variant is associated with the following publications: (PMID: 27008870, 24569164, 30702160) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change affects an acceptor splice site in intron 6 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (no rsID available, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). ClinVar contains an entry for this variant (Variation ID: 462651). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 7 (also known as exon 8 in the literature) (PMID: 24569164). 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

Benign

-0.0075

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.75

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.38

GERP RS

-2.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over