NM_007294.4:c.442-34C>T

Variant names:

• chr17-43099914-G-A
• rs799923
• NM_007294.4:c.442-34C>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.442-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,516,640 control chromosomes in the GnomAD database, including 35,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2485 hom., cov: 31)
  • Exomes 𝑓: 0.21 (33243 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:16 O:1
• Conservation: PhyloP100: -0.706
• Publications: 62 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-43099914-G-A is Benign according to our data. Variant chr17-43099914-G-A is described in ClinVar as Benign. ClinVar VariationId is 125864.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.442-34C>T		intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.442-34C>T		intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.442-34C>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.442-34C>T		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.442-34C>T		intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.442-34C>T		intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23922 AN: 152074 Hom.: 2483 Cov.: 31

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.173 AC: 43454 AN: 251154 AF XY: 0.182

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.000761

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.213 AC: 290248 AN: 1364448 Hom.: 33243 Cov.: 21 AF XY: 0.214 AC XY: 146025 AN XY: 683742

African (AFR) AF: 0.0343 AC: 1078 AN: 31414

American (AMR) AF: 0.0979 AC: 4362 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6494 AN: 25476

East Asian (EAS) AF: 0.000485 AC: 19 AN: 39144

South Asian (SAS) AF: 0.179 AC: 15057 AN: 84248

European-Finnish (FIN) AF: 0.183 AC: 9745 AN: 53150

Middle Eastern (MID) AF: 0.227 AC: 1270 AN: 5586

European-Non Finnish (NFE) AF: 0.236 AC: 241186 AN: 1023740

Other (OTH) AF: 0.193 AC: 11037 AN: 57150

GnomAD4 genome AF: 0.157 AC: 23920 AN: 152192 Hom.: 2485 Cov.: 31 AF XY: 0.154 AC XY: 11463 AN XY: 74408

African (AFR) AF: 0.0425 AC: 1767 AN: 41556

American (AMR) AF: 0.140 AC: 2139 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 927 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5186

South Asian (SAS) AF: 0.172 AC: 826 AN: 4814

European-Finnish (FIN) AF: 0.194 AC: 2051 AN: 10570

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15611 AN: 67996

Other (OTH) AF: 0.170 AC: 360 AN: 2114

Alfa AF: 0.205 Hom.: 8343

Bravo AF: 0.148

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Breast-ovarian cancer, familial, susceptibility to, 1 (5)
-	-	3	not provided (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.38
DANN	Benign	0.37
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs799923; hg19: chr17-41251931; COSMIC: COSV58783441;