17-43044897-G-A

Variant names:

• chr17-43044897-G-A
• rs8176319
• NM_007294.4:c.*781C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.*781C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 471,486 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (17 hom., cov: 30)
  • Exomes 𝑓: 0.00077 (3 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.0730
• Publications: 3 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 17-43044897-G-A is Benign according to our data. Variant chr17-43044897-G-A is described in ClinVar as Benign. ClinVar VariationId is 132778.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00667 (988/148092) while in subpopulation AFR AF = 0.0239 (945/39572). AF 95% confidence interval is 0.0226. There are 17 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*781C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.*781C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 987 AN: 147994 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00585

GnomAD2 exomes AF: 0.00138 AC: 169 AN: 122496 AF XY: 0.000998

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000569

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000529

GnomAD4 exome AF: 0.000767 AC: 248 AN: 323394 Hom.: 3 Cov.: 0 AF XY: 0.000563 AC XY: 102 AN XY: 181080

African (AFR) AF: 0.0222 AC: 201 AN: 9060

American (AMR) AF: 0.000648 AC: 17 AN: 26244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12330

East Asian (EAS) AF: 0.00 AC: 0 AN: 14932

South Asian (SAS) AF: 0.0000685 AC: 4 AN: 58406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12228

Middle Eastern (MID) AF: 0.00156 AC: 2 AN: 1282

European-Non Finnish (NFE) AF: 0.0000463 AC: 8 AN: 172874

Other (OTH) AF: 0.000998 AC: 16 AN: 16038

GnomAD4 genome AF: 0.00667 AC: 988 AN: 148092 Hom.: 17 Cov.: 30 AF XY: 0.00624 AC XY: 450 AN XY: 72068

African (AFR) AF: 0.0239 AC: 945 AN: 39572

American (AMR) AF: 0.00199 AC: 29 AN: 14554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67604

Other (OTH) AF: 0.00579 AC: 12 AN: 2072

Alfa AF: 0.00414 Hom.: 0

Bravo AF: 0.00760

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

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

Feb 17, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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 0.03049 (African), derived from 1000 genomes (2012-04-30). -

not specified Benign:1

Dec 11, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.62
PhyloP100		-0.073
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs8176319; hg19: chr17-41196914;