rs8176258

Variant names:

• chr17-43064004-G-A
• rs8176258
• NM_007294.4:c.5075-53C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43064004-G-A
• chr17-43064004-G-C
• chr17-43064004-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.5075-53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,533,560 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.024 (493 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: -0.152
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-43064004-G-A is Benign according to our data. Variant chr17-43064004-G-A is described in ClinVar as Benign. ClinVar VariationId is 125760.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2848/152268) while in subpopulation NFE AF = 0.0273 (1854/68008). AF 95% confidence interval is 0.0262. There are 42 homozygotes in GnomAd4. There are 1387 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR,AD gene

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.5075-53C>T		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5141-53C>T		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5141-53C>T		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.5075-53C>T		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5138-53C>T		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5075-53C>T		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2848 AN: 152150 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00785

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0238 AC: 32886 AN: 1381292 Hom.: 493 AF XY: 0.0232 AC XY: 16024 AN XY: 691340

African (AFR) AF: 0.00369 AC: 117 AN: 31712

American (AMR) AF: 0.0125 AC: 548 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 500 AN: 25540

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39142

South Asian (SAS) AF: 0.0116 AC: 976 AN: 83900

European-Finnish (FIN) AF: 0.0321 AC: 1699 AN: 52950

Middle Eastern (MID) AF: 0.00196 AC: 11 AN: 5626

European-Non Finnish (NFE) AF: 0.0267 AC: 27832 AN: 1040932

Other (OTH) AF: 0.0208 AC: 1200 AN: 57616

GnomAD4 genome AF: 0.0187 AC: 2848 AN: 152268 Hom.: 42 Cov.: 32 AF XY: 0.0186 AC XY: 1387 AN XY: 74450

African (AFR) AF: 0.00407 AC: 169 AN: 41558

American (AMR) AF: 0.0205 AC: 314 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4834

European-Finnish (FIN) AF: 0.0347 AC: 368 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1854 AN: 68008

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0183 Hom.: 18

Bravo AF: 0.0170

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	Breast-ovarian cancer, familial, susceptibility to, 1 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.54
PhyloP100		-0.15
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: rs8176258; hg19: chr17-41216021; COSMIC: COSV58789845;