ENST00000354071.8:n.4422A>C

Variant names:

• chr17-43091173-T-G
• rs799916
• ENST00000354071.8:n.4422A>C

Variant summary

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

The ENST00000354071.8(BRCA1):​n.4422A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 942,952 control chromosomes in the GnomAD database, including 72,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17270 hom., cov: 32)
  • Exomes 𝑓: 0.36 (55698 hom.)
• Consequence: BRCA1 ENST00000354071.8 non_coding_transcript_exon
• Clinical Significance: Benign reviewed by expert panel U:1 B:6 O:1
• Conservation: PhyloP100: -2.60
• Publications: 32 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=-0.95).
• BP6: Variant 17-43091173-T-G is Benign according to our data. Variant chr17-43091173-T-G is described in ClinVar as Benign. ClinVar VariationId is 125674.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4097-141A>C		intron_variant	Intron 10 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4097-141A>C		intron_variant	Intron 10 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68537 AN: 151926 Hom.: 17223 Cov.: 32

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.364 AC: 287828 AN: 790908 Hom.: 55698 Cov.: 11 AF XY: 0.369 AC XY: 151762 AN XY: 410750

African (AFR) AF: 0.687 AC: 13455 AN: 19586

American (AMR) AF: 0.355 AC: 12066 AN: 33944

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 7877 AN: 21246

East Asian (EAS) AF: 0.352 AC: 11606 AN: 33004

South Asian (SAS) AF: 0.526 AC: 34893 AN: 66312

European-Finnish (FIN) AF: 0.394 AC: 14246 AN: 36196

Middle Eastern (MID) AF: 0.420 AC: 1398 AN: 3330

European-Non Finnish (NFE) AF: 0.330 AC: 177702 AN: 539140

Other (OTH) AF: 0.382 AC: 14585 AN: 38150

GnomAD4 genome AF: 0.451 AC: 68641 AN: 152044 Hom.: 17270 Cov.: 32 AF XY: 0.453 AC XY: 33687 AN XY: 74314

African (AFR) AF: 0.687 AC: 28465 AN: 41462

American (AMR) AF: 0.376 AC: 5747 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1264 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1909 AN: 5166

South Asian (SAS) AF: 0.522 AC: 2513 AN: 4814

European-Finnish (FIN) AF: 0.404 AC: 4268 AN: 10552

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23192 AN: 67972

Other (OTH) AF: 0.427 AC: 900 AN: 2106

Alfa AF: 0.384 Hom.: 4289

Bravo AF: 0.455

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Aug 07, 2009

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 0.3304 (Asian), 0.2846 (African), 0.3681 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:2

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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	-0.95
CADD	Benign	0.0020
DANN	Benign	0.47
PhyloP100		-2.6
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: rs799916; hg19: chr17-41243190; COSMIC: COSV58794250; COSMIC: COSV58794250;