chr17-43044346-C-T

Position:

• chr17-43044346-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.*1332G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 496,390 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (35 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.282

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=-0.53).
• BP6: Variant 17-43044346-C-T is Benign according to our data. Variant chr17-43044346-C-T is described in ClinVar as [Benign]. Clinvar id is 209232.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43044346-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00966 (1472/152314) while in subpopulation NFE AF= 0.016 (1090/68030). AF 95% confidence interval is 0.0152. There are 13 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*1332G>A		3_prime_UTR_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.*1332G>A		3_prime_UTR_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1471 AN: 152196 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00960 AC: 1282 AN: 133592 Hom.: 12 AF XY: 0.00963 AC XY: 700 AN XY: 72662

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00609

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.000383

Gnomad SAS exome AF: 0.00339

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0105 AC: 3613 AN: 344076 Hom.: 35 Cov.: 0 AF XY: 0.00992 AC XY: 1897 AN XY: 191300

Gnomad4 AFR exome AF: 0.00291

Gnomad4 AMR exome AF: 0.00661

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000605

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.00356

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.00968

GnomAD4 genome AF: 0.00966 AC: 1472 AN: 152314 Hom.: 13 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74476

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0109 Hom.: 8

Bravo AF: 0.00953

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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 0.01187 (European), derived from 1000 genomes (2012-04-30). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 01, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.5
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176320; hg19: chr17-41196363;