17-43044346-C-T

Variant names:

• chr17-43044346-C-T
• rs8176320
• NM_007294.4:c.*1332G>A

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.*1332G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 496,390 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (35 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.282
• Publications: 8 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=-0.53).
• BP6: Variant 17-43044346-C-T is Benign according to our data. Variant chr17-43044346-C-T is described in ClinVar as Benign. ClinVar VariationId is 209232.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00966 (1472/152314) while in subpopulation NFE AF = 0.016 (1090/68030). AF 95% confidence interval is 0.0152. There are 13 homozygotes in GnomAd4. There are 664 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.*1332G>A		3_prime_UTR	Exon 23 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.*1332G>A		3_prime_UTR	Exon 24 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.*1332G>A		3_prime_UTR	Exon 24 of 24	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.*1332G>A		3_prime_UTR	Exon 23 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.*1332G>A		3_prime_UTR	Exon 24 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.*1332G>A		3_prime_UTR	Exon 23 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1471 AN: 152196 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00960 AC: 1282 AN: 133592 AF XY: 0.00963

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00609

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.000383

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0105 AC: 3613 AN: 344076 Hom.: 35 Cov.: 0 AF XY: 0.00992 AC XY: 1897 AN XY: 191300

African (AFR) AF: 0.00291 AC: 30 AN: 10314

American (AMR) AF: 0.00661 AC: 186 AN: 28144

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 57 AN: 13530

East Asian (EAS) AF: 0.0000605 AC: 1 AN: 16536

South Asian (SAS) AF: 0.00277 AC: 165 AN: 59492

European-Finnish (FIN) AF: 0.00356 AC: 45 AN: 12650

Middle Eastern (MID) AF: 0.00860 AC: 12 AN: 1396

European-Non Finnish (NFE) AF: 0.0160 AC: 2947 AN: 184456

Other (OTH) AF: 0.00968 AC: 170 AN: 17558

GnomAD4 genome AF: 0.00966 AC: 1472 AN: 152314 Hom.: 13 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74476

African (AFR) AF: 0.00310 AC: 129 AN: 41568

American (AMR) AF: 0.0120 AC: 184 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1090 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0111 Hom.: 9

Bravo AF: 0.00953

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.5
DANN	Benign	0.49
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs8176320; hg19: chr17-41196363;