17-43094861-C-G

Position:

• chr17-43094861-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.671-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:2
• Conservation: PhyloP100: 4.86

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.61248213 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43094861-C-G is Pathogenic according to our data. Variant chr17-43094861-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.671-1G>C		splice_acceptor_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.671-1G>C		splice_acceptor_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant causes a G to C nucleotide substitution at the -1 position of intron 9 of the BRCA1 gene. This variant is also known as IVS10-1G>C based on Breast Cancer Information Core (BIC) nomenclature. RNA studies on total RNA from carriers of BRCA1 c.671-2A>C and c.671-2A>G have reported the skipping of exon 10 and exons 8-10 that result in in-frame deletion and the out-of-frame skipping of exons 9 and 10 (PMID: 14513821, 24212087, 29774201, 30736279). Functional studies have reported that the skipping of exon 10, while reduces some BRCA1 function, does not completely abolish its activity for DNA damage repair and cell proliferation (PMID: 8972225, 11359908, 16949048). Collectively, the RNA and functional studies suggest that canonical splice site variants at intron 9 acceptor site may retain some BRCA1 activity similar to a leaky splice variant. This variant has been reported in an individual affected with breast cancer (PMID: 35220195). Other canonical splice site variants at the intron 9 splice acceptor site have been reported in 6 individuals affected with breast and/or ovarian cancer (PMID: 26911350, 28145423, 35918668) and multiple suspected breast and ovarian cancer families (PMID: 12960223, 29446198, 32614418) and individuals affected with lung cancer and melanoma (PMID: 33610559, 35712480). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 31, 2012	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.671-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 9 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor 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 this exon, which comprises over 50% of the BRCA1 protein, is absent in part or in whole in naturally occurring alternative splicing isoforms (Colombo M et al. Hum Mol Genet 2014 Jul;23(14):3666-80). Functional studies have shown that loss of this exon may impair cellular localization and have reduced, but not lost, DNA damage repair function (Thakur S et al. Mol Cell Biol 1997 Jan;17(1):444-52, Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15, Kim SS et al. Mol Cell Biol 2006 Sep;26(18):6983-92). Additionally, mouse embryos with homozygous BRCA1 coding exon 9 deletions survive longer than BRCA1-null embryos, suggesting protein without exon 9 may still be able to perform some BRCA1 essential functions (Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15). Based on the majority of available evidence to date, this variant is likely pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2023

Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 35220195). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 91663). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). -

not provided Uncertain:1

Uncertain significance, flagged submission

clinical testing

GeneDx

Nov 09, 2015

This variant is denoted BRCA1 c.671-1G>C or IVS9-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 9 of the BRCA1 gene. Using alternate nomenclature this variant would be defined as BRCA1 790-1G>C or IVS10-1G>C. This variant has not, to our knowledge, been published in the literature. BRCA1 c.671-1G>C destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing. However, the transcript predicted to result from this variant, an in-frame deletion of exon 10, is a splicing isoform noted to be present at low levels in normal breast tissue and peripheral blood lymphocytes from control individuals (Brandao 2011, Colombo 2014). Rosenthal et al. (2015) reported nearby BRCA1 variants predicted to impact splicing as being clinically insignificant based on a high frequency in control populations, co-occurrence with known pathogenic BRCA1/2 variants, and inconsistent segregation and phenotype data. One such variant, BRCA1 c.591C>T (p.Cys197Cys), was reported by Dosil et al. (2010) to induce exon 9 (now referred to as exon 8) skipping while simultaneously increasing expression of other naturally occurring splicing isoforms which preserve the open reading frame. Based on these findings, Rosenthal et al. (2015) proposed that alternative transcripts may rescue" variants that disrupt splicing for what are now defined as exons 8 and 9, and a similar phenomenon could occur with BRCA1 c.671-1G>C. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Despite this variant's predicted effect on splicing, based on currently available evidence we consider BRCA1 c.671-1G>C to be a variant of uncertain significance." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
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

Other links and lift over

dbSNP: rs80358020; hg19: chr17-41246878;