rs80358022

Variant names:

• chr17-43076474-T-C
• rs80358022
• NM_007294.4:c.4484+14A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007294.4(BRCA1):​c.4484+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:22
• Conservation: PhyloP100: -0.0590
• Publications: 9 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-43076474-T-C is Benign according to our data. Variant chr17-43076474-T-C is described in ClinVar as Benign. ClinVar VariationId is 55210.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000348 (53/152268) while in subpopulation EAS AF = 0.00985 (51/5180). AF 95% confidence interval is 0.00769. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4484+14A>G		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4550+14A>G		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4550+14A>G		intron	N/A	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4484+14A>G		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4547+14A>G		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4484+14A>G		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000789 AC: 198 AN: 251098 AF XY: 0.000832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00941

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1460876 Hom.: 0 Cov.: 31 AF XY: 0.000326 AC XY: 237 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00855 AC: 339 AN: 39630

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86240

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111480

Other (OTH) AF: 0.000530 AC: 32 AN: 60364

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.000416 AC XY: 31 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00985 AC: 51 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000499

Asia WGS AF: 0.00636 AC: 22 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	5	Breast-ovarian cancer, familial, susceptibility to, 1 (6)
-	-	6	not specified (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.059
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		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: rs80358022; hg19: chr17-41228491; COSMIC: COSV58799376; COSMIC: COSV58799376;