17-43104860-A-G

Position:

• chr17-43104860-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.301+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000906 in 1,610,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001946
• Clinical Significance: Benign reviewed by expert panel U:2 B:15 O:1
• Conservation: PhyloP100: 1.55

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-43104860-A-G is Benign according to our data. Variant chr17-43104860-A-G is described in ClinVar as [Benign]. Clinvar id is 125666.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104860-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.301+8T>C		splice_region_variant, intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.301+8T>C		splice_region_variant, intron_variant		1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251170 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135762

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000376

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: 0.0000494 AC: 72 AN: 1458668 Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31 AN XY: 725902

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.000246

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: 9.01e-7

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74476

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000491

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:15 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:3 Other:1

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	Variant allele has no predicted coding change (intronic variant), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00148 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13). -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 30, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2016	Variant summary: c.301+8T>C affects a non-conserved nucleotide, resulting in an intronic change. Mutation taster predicts benign outcome. The variant is located in a position not widely known to affect splicing and 5/5 splicing prediction programs suggest no effect on splicing. This variant was found in 17/121300 control chromosomes at a frequency of 0.0001401, predominantly observed in the African subpopulation of ExAC with observed MAF of 0.001252, which exceeds the maximal expected frequency of a pathogenic allele (0.0010005), suggesting that the variant might be a polymorphism found in population(s) of African origin. Although the variant has been reported in subjects from HBOC families, there is no cosegregation study to show whether the variant could have explained the phenotype. BIC cites variant in one individual who also carried a potentially pathogenic variant BRCA1 c.302-1G>A. In addition, multiple clinical laboratories classified this variant as benign. Considering all, this variant is classified as Likely Benign until more information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 06, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2022	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.1
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358101; hg19: chr17-41256877;