17-43067543-C-T

Variant names:

• chr17-43067543-C-T
• rs8176235
• NM_007294.4:c.5074+65G>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+65G>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 1,362,902 control chromosomes in the GnomAD database, including 51,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5015 hom., cov: 30)
  • Exomes 𝑓: 0.27 (46555 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4 O:1
• Conservation: PhyloP100: 0.167
• Publications: 18 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=-0.9).
• BP6: Variant 17-43067543-C-T is Benign according to our data. Variant chr17-43067543-C-T is described in ClinVar as Benign. ClinVar VariationId is 127126.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5074+65G>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+65G>A		intron_variant	Intron 16 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37549 AN: 151896 Hom.: 5009 Cov.: 30

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.270 AC: 327234 AN: 1210886 Hom.: 46555 Cov.: 16 AF XY: 0.277 AC XY: 170284 AN XY: 613718

African (AFR) AF: 0.163 AC: 4608 AN: 28294

American (AMR) AF: 0.280 AC: 12178 AN: 43560

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6493 AN: 24464

East Asian (EAS) AF: 0.353 AC: 13435 AN: 38048

South Asian (SAS) AF: 0.462 AC: 37369 AN: 80804

European-Finnish (FIN) AF: 0.309 AC: 16118 AN: 52084

Middle Eastern (MID) AF: 0.297 AC: 1571 AN: 5282

European-Non Finnish (NFE) AF: 0.250 AC: 221486 AN: 886504

Other (OTH) AF: 0.270 AC: 13976 AN: 51846

GnomAD4 genome AF: 0.247 AC: 37564 AN: 152016 Hom.: 5015 Cov.: 30 AF XY: 0.254 AC XY: 18862 AN XY: 74296

African (AFR) AF: 0.169 AC: 7010 AN: 41482

American (AMR) AF: 0.268 AC: 4095 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1911 AN: 5144

South Asian (SAS) AF: 0.461 AC: 2222 AN: 4824

European-Finnish (FIN) AF: 0.307 AC: 3245 AN: 10556

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17314 AN: 67958

Other (OTH) AF: 0.267 AC: 562 AN: 2108

Alfa AF: 0.244 Hom.: 2095

Bravo AF: 0.234

Asia WGS AF: 0.390 AC: 1356 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

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

not specified Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 0.3322 (Asian), 0.1402 (African), 0.2744 (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	-0.90
CADD	Benign	5.1
DANN	Benign	0.74
PhyloP100		0.17
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: rs8176235; hg19: chr17-41219560; COSMIC: COSV58786515;