rs80357906

Variant names:

• chr17-43057062-T-TG
• rs80357906
• NM_007294.4:c.5266dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001407581.1(BRCA1):​c.5332dupC​(p.Gln1778ProfsTer74) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1778Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: BRCA1 NM_001407581.1 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:84 U:1 O:3
• Conservation: PhyloP100: 2.46
• Publications: 428 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):

• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43057062-T-TG is Pathogenic according to our data. Variant chr17-43057062-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 17677.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407581.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5266dupC	p.Gln1756ProfsTer74	frameshift	Exon 19 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5332dupC	p.Gln1778ProfsTer74	frameshift	Exon 20 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5332dupC	p.Gln1778ProfsTer74	frameshift	Exon 20 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5266dupC	p.Gln1756ProfsTer74	frameshift	Exon 19 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5329dupC	p.Gln1777ProfsTer74	frameshift	Exon 20 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5266dupC	p.Gln1756ProfsTer74	frameshift	Exon 19 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251494 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727176

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111888

Other (OTH) AF: 0.000149 AC: 9 AN: 60388

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
41	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (41)
16	-	-	not provided (17)
8	-	-	Hereditary breast ovarian cancer syndrome (9)
4	-	-	Familial cancer of breast (4)
3	-	-	Breast and/or ovarian cancer (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Ovarian neoplasm (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	BRCA1-related disorder (1)
1	-	-	Breast neoplasm (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)
-	1	-	Malignant tumor of breast (1)
1	-	-	Punctate palmoplantar keratoderma type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs80357906; hg19: chr17-41209079;