rs373413425

Variant names:

• chr17-43104072-AAAAAAAAAGAAAAG-A
• rs373413425
• NM_007294.4:c.441+36_441+49delCTTTTCTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.441+36_441+49delCTTTTCTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7278 hom., cov: 0)
  • Exomes 𝑓: 0.33 (75684 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.85
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 17-43104072-AAAAAAAAAGAAAAG-A is Benign according to our data. Variant chr17-43104072-AAAAAAAAAGAAAAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.441+36_441+49delCTTTTCTTTTTTTT		intron_variant	Intron 6 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.441+36_441+49delCTTTTCTTTTTTTT		intron_variant	Intron 6 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.307 AC: 45436 AN: 147950 Hom.: 7273 Cov.: 0

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.336

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.259 AC: 43519 AN: 167932 AF XY: 0.269

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.294

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.253

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.328 AC: 454824 AN: 1388516 Hom.: 75684 AF XY: 0.333 AC XY: 230721 AN XY: 692398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.219 AC: 6787 AN: 31012

American (AMR) AF: 0.320 AC: 12508 AN: 39122

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 8980 AN: 24954

East Asian (EAS) AF: 0.348 AC: 13588 AN: 39036

South Asian (SAS) AF: 0.492 AC: 38883 AN: 79010

European-Finnish (FIN) AF: 0.378 AC: 17943 AN: 47454

Middle Eastern (MID) AF: 0.360 AC: 1910 AN: 5312

European-Non Finnish (NFE) AF: 0.315 AC: 335284 AN: 1065052

Other (OTH) AF: 0.329 AC: 18941 AN: 57564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.307 AC: 45460 AN: 148046 Hom.: 7278 Cov.: 0 AF XY: 0.312 AC XY: 22483 AN XY: 72026

African (AFR) AF: 0.222 AC: 9044 AN: 40736

American (AMR) AF: 0.321 AC: 4755 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1218 AN: 3422

East Asian (EAS) AF: 0.361 AC: 1827 AN: 5054

South Asian (SAS) AF: 0.485 AC: 2254 AN: 4646

European-Finnish (FIN) AF: 0.379 AC: 3611 AN: 9526

Middle Eastern (MID) AF: 0.338 AC: 96 AN: 284

European-Non Finnish (NFE) AF: 0.326 AC: 21732 AN: 66640

Other (OTH) AF: 0.328 AC: 669 AN: 2038

Alfa AF: 0.150 Hom.: 651

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs373413425; hg19: chr17-41256089;