chr17-43104083-AAAG-A

Position:

• chr17-43104083-AAAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000357654.9(BRCA1):​c.441+36_441+38del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,115,902 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (16 hom.)
• Consequence: BRCA1 ENST00000357654.9 intron
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.583

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 -16 ACMG points.

• BP6: Variant 17-43104083-AAAG-A is Benign according to our data. Variant chr17-43104083-AAAG-A is described in ClinVar as [Benign]. Clinvar id is 225704.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104083-AAAG-A is described in Lovd as [Benign]. Variant chr17-43104083-AAAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (128/72166) while in subpopulation SAS AF= 0.0136 (18/1320). AF 95% confidence interval is 0.00881. There are 1 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.441+36_441+38del		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.441+36_441+38del		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 128 AN: 72106 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00268

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.00216

GnomAD3 exomes AF: 0.00865 AC: 1657 AN: 191546 Hom.: 36 AF XY: 0.00829 AC XY: 855 AN XY: 103078

Gnomad AFR exome AF: 0.00607

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00466

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00775

GnomAD4 exome AF: 0.00192 AC: 2002 AN: 1043736 Hom.: 16 AF XY: 0.00205 AC XY: 1025 AN XY: 500924

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.000550

Gnomad4 EAS exome AF: 0.00177

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.00984

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.00332

GnomAD4 genome AF: 0.00177 AC: 128 AN: 72166 Hom.: 1 Cov.: 0 AF XY: 0.00173 AC XY: 60 AN XY: 34618

Gnomad4 AFR AF: 0.00203

Gnomad4 AMR AF: 0.00174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.0136

Gnomad4 FIN AF: 0.00268

Gnomad4 NFE AF: 0.00111

Gnomad4 OTH AF: 0.00216

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 28, 2016	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3559 (European), 0.3321 (African), 0.4006 (Admixed American/Latino), 0.3899 (East Asian), 0.5204 (South Asian), derived from 1000 genomes (2013-05-02). -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 14, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 c.441+36_441+38delCTT variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, LOVD, COSMIC, the ClinVar database, GeneInsight VariantWire database and the BIC database. The variant was identified in dbSNP (ID: rs147856441) and UMD (16X as a neutral variant). This variant was also identified in the 1000 Genomes Project in 1977 of 5008 chromosomes (frequency: 0.395), increasing the likelihood this could be a low frequency benign variant. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2013

The variant is found in HEREDICANCER panel(s). -

Computational scores

Source: dbNSFP v4.3

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: rs147856441; hg19: chr17-41256100;