chr17-43044391-G-A

Position:

• chr17-43044391-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.*1287C>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 0.339 in 504,982 control chromosomes in the GnomAD database, including 30,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7721 hom., cov: 32)
  • Exomes 𝑓: 0.35 (23067 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel P:1 B:6
• Conservation: PhyloP100: 0.953

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-43044391-G-A is Benign according to our data. Variant chr17-43044391-G-A is described in ClinVar as [Benign]. Clinvar id is 132777.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43044391-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.*1287C>T		3_prime_UTR_variant	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.*1287C>T		3_prime_UTR_variant	23/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47216 AN: 151928 Hom.: 7718 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.342 AC: 46670 AN: 136324 Hom.: 8695 AF XY: 0.357 AC XY: 26442 AN XY: 74056

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.382

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.351 AC: 123858 AN: 352934 Hom.: 23067 Cov.: 0 AF XY: 0.366 AC XY: 71686 AN XY: 195766

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.370

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.389

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.311 AC: 47237 AN: 152048 Hom.: 7721 Cov.: 32 AF XY: 0.316 AC XY: 23512 AN XY: 74320

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.331

Alfa AF: 0.317 Hom.: 8859

Bravo AF: 0.292

Asia WGS AF: 0.408 AC: 1416 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -
Likely risk allele, no assertion criteria provided	research	School of Public Health, China Medical University	Oct 01, 2019	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3339 (Asian), 0.2114 (African), 0.3602 (European), derived from 1000 genomes (2012-04-30).t Publications:pubmed 33986610,32414209,29963045 -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	1kG or ESP high frequency. -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3339 (Asian), 0.2114 (African), 0.3602 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneKor MSA

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12516; hg19: chr17-41196408; COSMIC: COSV58790086; COSMIC: COSV58790086;