rs2236762

Positions:

• chr17-43074658-A-T

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.4485-137T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 775,348 control chromosomes in the GnomAD database, including 62,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17307 hom., cov: 31)
  • Exomes 𝑓: 0.37 (45136 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.576

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=-0.9).
• BP6: Variant 17-43074658-A-T is Benign according to our data. Variant chr17-43074658-A-T is described in ClinVar as [Benign]. Clinvar id is 209375.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074658-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4485-137T>A		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4485-137T>A		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68553 AN: 151870 Hom.: 17260 Cov.: 31

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.426

GnomAD4 exome AF: 0.370 AC: 230913 AN: 623360 Hom.: 45136 AF XY: 0.376 AC XY: 124821 AN XY: 331682

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.352

Gnomad4 ASJ exome AF: 0.372

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.527

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.452 AC: 68657 AN: 151988 Hom.: 17307 Cov.: 31 AF XY: 0.454 AC XY: 33704 AN XY: 74290

Gnomad4 AFR AF: 0.688

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.521

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.429

Alfa AF: 0.400 Hom.: 1651

Bravo AF: 0.455

Asia WGS AF: 0.466 AC: 1621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

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

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 0.3304 (Asian), 0.2846 (African), 0.3668 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.078
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs2236762; hg19: chr17-41226675; COSMIC: COSV58801011; COSMIC: COSV58801011;