NM_007294.4:c.4357+117G>A

Variant names:

• chr17-43082287-C-T
• rs3737559
• NM_007294.4:c.4357+117G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.4357+117G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 1,141,584 control chromosomes in the GnomAD database, including 4,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.070 (452 hom., cov: 32)
  • Exomes 𝑓: 0.082 (3680 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: -0.445
• Publications: 45 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=-0.85).
• BP6: Variant 17-43082287-C-T is Benign according to our data. Variant chr17-43082287-C-T is described in ClinVar as Benign. ClinVar VariationId is 125708.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4357+117G>A		intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.4357+117G>A		intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.4357+117G>A		intron	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4357+117G>A		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.4357+117G>A		intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.4357+117G>A		intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10731 AN: 152132 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0917

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.0733

GnomAD4 exome AF: 0.0824 AC: 81503 AN: 989334 Hom.: 3680 AF XY: 0.0836 AC XY: 41808 AN XY: 500118

African (AFR) AF: 0.0293 AC: 685 AN: 23376

American (AMR) AF: 0.0359 AC: 1164 AN: 32438

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 1655 AN: 18574

East Asian (EAS) AF: 0.0991 AC: 3678 AN: 37130

South Asian (SAS) AF: 0.105 AC: 6692 AN: 63844

European-Finnish (FIN) AF: 0.129 AC: 5150 AN: 39908

Middle Eastern (MID) AF: 0.0773 AC: 323 AN: 4180

European-Non Finnish (NFE) AF: 0.0809 AC: 58751 AN: 725884

Other (OTH) AF: 0.0774 AC: 3405 AN: 44000

GnomAD4 genome AF: 0.0705 AC: 10728 AN: 152250 Hom.: 452 Cov.: 32 AF XY: 0.0720 AC XY: 5359 AN XY: 74426

African (AFR) AF: 0.0275 AC: 1143 AN: 41560

American (AMR) AF: 0.0494 AC: 754 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3472

East Asian (EAS) AF: 0.0919 AC: 476 AN: 5178

South Asian (SAS) AF: 0.118 AC: 570 AN: 4826

European-Finnish (FIN) AF: 0.123 AC: 1298 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0872 AC: 5934 AN: 68028

Other (OTH) AF: 0.0726 AC: 153 AN: 2108

Alfa AF: 0.0768 Hom.: 923

Bravo AF: 0.0602

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain: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 0.08566 (Asian), 0.03862 (African), 0.07916 (European), derived from 1000 genomes (2012-04-30).

Aug 07, 2009

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.49
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3737559; hg19: chr17-41234304; COSMIC: COSV58789590; COSMIC: COSV58789590;