rs1351019392

Variant names:

• chr17-43099881-C-A
• rs1351019392
• NM_007294.4:c.442-1G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43099881-C-A
• chr17-43099881-C-G
• chr17-43099881-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

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 Uncertain significance (★★★).

• 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:2 U:7
• Conservation: PhyloP100: -0.276
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018955652 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.442-1G>T		splice_acceptor_variant, intron_variant	Intron 6 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.442-1G>T		splice_acceptor_variant, intron_variant	Intron 6 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251404 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454248 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723960

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.0000448 AC: 2 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105126

Other (OTH) AF: 0.00 AC: 0 AN: 60132

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2 Uncertain:2

Feb 01, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 07, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2020

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 12, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Jul 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 06, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Uncertain:1

Jan 29, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disruption of this splice site is associated with deletion of 1 amino acid, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 24569164; internal data). 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	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.75
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.38	N
PhyloP100		-0.28
GERP RS		-2.1
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1351019392; hg19: chr17-41251898;