17-43076616-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_007294.4(BRCA1):c.4358-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 splice_acceptor
• Scores: Splicing: ADA: 0.9217
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.44

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 10 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.9, offset of -1, new splice context is: gttttctcattccatttaAGgca. 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4358-2A>G		splice_acceptor_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4358-2A>G		splice_acceptor_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria The BRCA1 c.4358-2A>G variant was found in the splice junction of exon 13 of the BRCA1 gene. Based on the position of this variant, a splice site receptor, it can potentially interfere with splicing which is an established disease mechanism (PVS1 Pathogenic Very Strong). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 3 pathogenic predictions from EIGEN, FATHMM-MKL and MutationTaster versus 1 benign prediction from DANN support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a female patient with unilateral breast cancer and ovarian cancer at age 40 and with a strong family history of cancer (PP4 Pathogenic Supporting). Therefore, this variant was classified as a Likely Pathogenic. Therefore, this variant was classified as a Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 17, 2017

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.4358-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 12 in the BRCA1 gene. One study reported this alteration in 1 out of 76 individuals with suspected hereditary breast and/or ovarian cancer (Moradian MM. Hum Genome Var. 2021 Feb;8(1):9). In addition, this alteration was reported in several affected members of a Han Chinese family with a history of ovarian and rectal cancers (Hu PZ et al. Curr Med Sci, 2022 Jun;42:666-672). This nucleotide position is highly conserved in available vertebrate species, and is part of an acceptor site that has a known alternate acceptor site 3 nucleotides downstream of the native site, producing a transcript that is predicted to result in the in-frame loss of a single amino acid at the beginning of coding exon 12 (This transcript is also called Δ14p in some literature, eg Colombo M et al. Hum Mol Genet, 2014 Jul;23:3666-80). The clinical impact of alterations impacting this acceptor site is not clear. In silico splice site analysis predicts that this alteration will also result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	34
Dann	Benign	0.89
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		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: rs1555582723; hg19: chr17-41228633;