chr17-43094862-T-G

Variant names:

• chr17-43094862-T-G
• rs80358108
• NM_007294.4:c.671-2A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.671-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000687 in 1,454,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.92
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.61266094 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 17-43094862-T-G is Pathogenic according to our data. Variant chr17-43094862-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.671-2A>C		splice_acceptor_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.671-2A>C		splice_acceptor_variant, intron_variant	Intron 9 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236750 AF XY: 0.00

Gnomad AFR exome AF: 0.0000690

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.87e-7 AC: 1 AN: 1454622 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 85540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107970

Other (OTH) AF: 0.00 AC: 0 AN: 60104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jun 21, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 14, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

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

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 9 in the BRCA1 gene. This mutation was reported in a high-risk breast cancer family and was shown to result in an aberrant RNA splicing transcript without coding exon 9 (Exon 11 in the literature, Keaton JC et al. J. Hum. Genet. 2003 ; 48(8):399-403). 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 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. -

Jan 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to C nucleotide substitution at the -2 position of intron 9 of the BRCA1 gene. This variant is also known as IVS10-2A>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. 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, 35220195, 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 been reported as a reduced penetrance pathogenic variant (PMID: 39488595). This variant has been identified in 1/236750 chromosomes 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 Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Mar 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 55663). Studies have shown that disruption of this splice site results in multiple aberrant transcripts that delete exon 10 (referred to as exon 11) (PMID: 14513821). This variant disrupts the nuclear localization signal, DNA binding domain and coiled-coil domain of BRCA1, which mediate interactions with RAD51, RAD50 and PALB2 (PMID: 25652403, 22737296). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Benign	0.97
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.9
GERP RS		4.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: -2

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

Other links and lift over

dbSNP: rs80358108; hg19: chr17-41246879;