rs8176100

Variant names:

• chr17-43115615-G-A
• rs8176100
• NM_007294.4:c.134+111C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43115615-G-A
• chr17-43115615-G-C
• chr17-43115615-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.134+111C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,067,862 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (11 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.410
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-43115615-G-A is Benign according to our data. Variant chr17-43115615-G-A is described in ClinVar as Benign. ClinVar VariationId is 209535.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00124 (189/152024) while in subpopulation EAS AF = 0.0187 (97/5182). AF 95% confidence interval is 0.0157. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.134+111C>T		intron_variant	Intron 3 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.134+111C>T		intron_variant	Intron 3 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 151908 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00136 AC: 1245 AN: 915838 Hom.: 11 AF XY: 0.00138 AC XY: 647 AN XY: 468824

African (AFR) AF: 0.0000477 AC: 1 AN: 20970

American (AMR) AF: 0.000204 AC: 6 AN: 29370

Ashkenazi Jewish (ASJ) AF: 0.00309 AC: 65 AN: 21058

East Asian (EAS) AF: 0.0212 AC: 698 AN: 32908

South Asian (SAS) AF: 0.00134 AC: 87 AN: 65148

European-Finnish (FIN) AF: 0.00258 AC: 117 AN: 45350

Middle Eastern (MID) AF: 0.000475 AC: 2 AN: 4212

European-Non Finnish (NFE) AF: 0.000339 AC: 222 AN: 655290

Other (OTH) AF: 0.00113 AC: 47 AN: 41532

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152024 Hom.: 2 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74316

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4804

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67988

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000846

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01049 (Asian), derived from 1000 genomes (2012-04-30).

Hereditary breast ovarian cancer syndrome Benign:1

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.8
DANN	Benign	0.69
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs8176100; hg19: chr17-41267632;