17-43115746-C-T

Variant names:

• chr17-43115746-C-T
• rs1800062
• NM_007294.4:c.114G>A

Variant summary

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

The NM_001407694.1(BRCA1):​c.-144G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,626 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0029 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (80 hom.)
• Consequence: BRCA1 NM_001407694.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:33
• Conservation: PhyloP100: -0.475
• Publications: 31 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-43115746-C-T is Benign according to our data. Variant chr17-43115746-C-T is described in ClinVar as Benign. ClinVar VariationId is 54146.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407694.1. 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.114G>A	p.Lys38Lys	synonymous	Exon 3 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407694.1		c.-144G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001394623.1	A0A9Y1QQK3
	BRCA1	NM_001407695.1		c.-148G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001394624.1	P38398-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.114G>A	p.Lys38Lys	synonymous	Exon 3 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.114G>A	p.Lys38Lys	synonymous	Exon 3 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.114G>A	p.Lys38Lys	synonymous	Exon 3 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152104 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00444 AC: 1113 AN: 250826 AF XY: 0.00362

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0393

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00190 AC: 2773 AN: 1461404 Hom.: 80 Cov.: 30 AF XY: 0.00180 AC XY: 1306 AN XY: 726984

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.00965 AC: 431 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0550 AC: 2180 AN: 39670

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111778

Other (OTH) AF: 0.00200 AC: 121 AN: 60374

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152222 Hom.: 9 Cov.: 32 AF XY: 0.00376 AC XY: 280 AN XY: 74418

African (AFR) AF: 0.000337 AC: 14 AN: 41536

American (AMR) AF: 0.0132 AC: 202 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0442 AC: 229 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000502 Hom.: 2

Bravo AF: 0.00320

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	7	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
-	-	6	not provided (6)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.2
DANN	Benign	0.54
PhyloP100		-0.47
Mutation Taster		=98/2	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: rs1800062; hg19: chr17-41267763; COSMIC: COSV100523636;