NM_007294.4:c.*1287C>T

Variant names:

• chr17-43044391-G-A
• rs12516
• NM_007294.4:c.*1287C>T

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.*1287C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 504,982 control chromosomes in the GnomAD database, including 30,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7721 hom., cov: 32)
  • Exomes 𝑓: 0.35 (23067 hom.)
• Consequence: BRCA1 NM_007294.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel P:1 B:6
• Conservation: PhyloP100: 0.953
• Publications: 49 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=-0.8).
• BP6: Variant 17-43044391-G-A is Benign according to our data. Variant chr17-43044391-G-A is described in ClinVar as Benign. ClinVar VariationId is 132777.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.*1287C>T		3_prime_UTR	Exon 23 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.*1287C>T		3_prime_UTR	Exon 24 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.*1287C>T		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.*1287C>T		3_prime_UTR	Exon 23 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.*1287C>T		3_prime_UTR	Exon 24 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.*1287C>T		3_prime_UTR	Exon 23 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47216 AN: 151928 Hom.: 7718 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.342 AC: 46670 AN: 136324 AF XY: 0.357

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.351 AC: 123858 AN: 352934 Hom.: 23067 Cov.: 0 AF XY: 0.366 AC XY: 71686 AN XY: 195766

African (AFR) AF: 0.234 AC: 2529 AN: 10786

American (AMR) AF: 0.220 AC: 6304 AN: 28712

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 5168 AN: 13984

East Asian (EAS) AF: 0.359 AC: 6225 AN: 17340

South Asian (SAS) AF: 0.498 AC: 29918 AN: 60056

European-Finnish (FIN) AF: 0.389 AC: 4968 AN: 12786

Middle Eastern (MID) AF: 0.378 AC: 546 AN: 1444

European-Non Finnish (NFE) AF: 0.328 AC: 62130 AN: 189600

Other (OTH) AF: 0.333 AC: 6070 AN: 18226

GnomAD4 genome AF: 0.311 AC: 47237 AN: 152048 Hom.: 7721 Cov.: 32 AF XY: 0.316 AC XY: 23512 AN XY: 74320

African (AFR) AF: 0.232 AC: 9640 AN: 41486

American (AMR) AF: 0.272 AC: 4142 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3466

East Asian (EAS) AF: 0.373 AC: 1927 AN: 5172

South Asian (SAS) AF: 0.493 AC: 2378 AN: 4826

European-Finnish (FIN) AF: 0.405 AC: 4283 AN: 10568

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22565 AN: 67964

Other (OTH) AF: 0.331 AC: 697 AN: 2108

Alfa AF: 0.309 Hom.: 13957

Bravo AF: 0.292

Asia WGS AF: 0.408 AC: 1416 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
-	-	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.57
PhyloP100		0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=94/6	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12516; hg19: chr17-41196408; COSMIC: COSV58790086; COSMIC: COSV58790086;