17-43067324-G-T

Variant names:

• chr17-43067324-G-T
• rs11654396
• NM_007294.4:c.5074+284C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.5074+284C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 282,550 control chromosomes in the GnomAD database, including 11,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4355 hom., cov: 24)
  • Exomes 𝑓: 0.30 (7022 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3 O:1
• Conservation: PhyloP100: 0.548
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-43067324-G-T is Benign according to our data. Variant chr17-43067324-G-T is described in ClinVar as Benign. ClinVar VariationId is 127127.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5074+284C>A		intron_variant	Intron 16 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5074+284C>A		intron_variant	Intron 16 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.238 AC: 34470 AN: 144560 Hom.: 4347 Cov.: 24

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.298 AC: 41158 AN: 137920 Hom.: 7022 Cov.: 0 AF XY: 0.316 AC XY: 23749 AN XY: 75042

African (AFR) AF: 0.170 AC: 607 AN: 3564

American (AMR) AF: 0.274 AC: 1482 AN: 5408

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 869 AN: 3496

East Asian (EAS) AF: 0.187 AC: 1079 AN: 5758

South Asian (SAS) AF: 0.475 AC: 11789 AN: 24832

European-Finnish (FIN) AF: 0.326 AC: 2181 AN: 6686

Middle Eastern (MID) AF: 0.323 AC: 169 AN: 524

European-Non Finnish (NFE) AF: 0.263 AC: 21142 AN: 80490

Other (OTH) AF: 0.257 AC: 1840 AN: 7162

GnomAD4 genome AF: 0.238 AC: 34485 AN: 144630 Hom.: 4355 Cov.: 24 AF XY: 0.245 AC XY: 17131 AN XY: 69828

African (AFR) AF: 0.158 AC: 6093 AN: 38590

American (AMR) AF: 0.264 AC: 3689 AN: 13960

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 910 AN: 3448

East Asian (EAS) AF: 0.188 AC: 912 AN: 4846

South Asian (SAS) AF: 0.431 AC: 1971 AN: 4568

European-Finnish (FIN) AF: 0.330 AC: 3055 AN: 9246

Middle Eastern (MID) AF: 0.284 AC: 76 AN: 268

European-Non Finnish (NFE) AF: 0.255 AC: 17056 AN: 66814

Other (OTH) AF: 0.255 AC: 508 AN: 1990

Alfa AF: 0.230 Hom.: 561

Bravo AF: 0.217

Asia WGS AF: 0.287 AC: 998 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1626 (Asian), 0.1138 (African), 0.2704 (European), derived from 1000 genomes (2012-04-30).

Familial cancer of breast Other:1

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11654396; hg19: chr17-41219341;