rs80358111

Variant names:

• chr17-43076624-G-A
• rs80358111
• NM_007294.4:c.4358-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43076624-G-A
• chr17-43076624-G-C
• chr17-43076624-G-T

Variant summary

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

The NM_007294.4(BRCA1):​c.4358-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Scores: Splicing: ADA: 0.9916
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.61
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 17-43076624-G-A is Benign according to our data. Variant chr17-43076624-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 125710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4358-10C>T		intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.4424-10C>T		intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.4424-10C>T		intron	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4358-10C>T		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.4424-13C>T		intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.4358-10C>T		intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152058 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250454 AF XY: 0.000273

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000242 AC: 354 AN: 1460234 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 726486

African (AFR) AF: 0.0000897 AC: 3 AN: 33444

American (AMR) AF: 0.00119 AC: 53 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000253 AC: 281 AN: 1111220

Other (OTH) AF: 0.000265 AC: 16 AN: 60356

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74408

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.000852 AC: 13 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000268

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
-	-	4	not provided (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.70
PhyloP100		1.6
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
Splicevardb		1.0
SpliceAI score (max)		0.10		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: rs80358111; hg19: chr17-41228641; COSMIC: COSV58791536; COSMIC: COSV58791536;