rs572766355

Variant names:

• chr17-43056992-G-GGGAGTGGAATAC
• rs572766355
• NM_007294.4:c.5277+48_5277+59dupGTATTCCACTCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5277+48_5277+59dupGTATTCCACTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,469,986 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (1 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.590
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 -8 ACMG points.

• BP6: Variant 17-43056992-G-GGGAGTGGAATAC is Benign according to our data. Variant chr17-43056992-G-GGGAGTGGAATAC is described in ClinVar as Benign. ClinVar VariationId is 433729.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5277+48_5277+59dupGTATTCCACTCC		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5343+48_5343+59dupGTATTCCACTCC		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5343+48_5343+59dupGTATTCCACTCC		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.5277+59_5277+60insGTATTCCACTCC		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5340+59_5340+60insGTATTCCACTCC		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5277+59_5277+60insGTATTCCACTCC		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152130 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00239 AC: 3150 AN: 1317738 Hom.: 1 AF XY: 0.00232 AC XY: 1542 AN XY: 663324

African (AFR) AF: 0.000492 AC: 15 AN: 30472

American (AMR) AF: 0.000786 AC: 35 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.00 AC: 0 AN: 39056

South Asian (SAS) AF: 0.0000960 AC: 8 AN: 83318

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00300 AC: 2940 AN: 980770

Other (OTH) AF: 0.00130 AC: 72 AN: 55556

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152248 Hom.: 1 Cov.: 31 AF XY: 0.00155 AC XY: 115 AN XY: 74422

African (AFR) AF: 0.000578 AC: 24 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00323 AC: 220 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00184 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs572766355;

hg19: chr17-41209009;