rs149402012

Variant names:

• chr17-43124076-G-A
• rs149402012
• NM_007294.4:c.21C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43124076-G-A
• chr17-43124076-G-C
• chr17-43124076-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_007294.4(BRCA1):​c.21C>T​(p.Arg7Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,613,436 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. R7R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:22
• Conservation: PhyloP100: -2.72
• Publications: 13 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

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-43124076-G-A is Benign according to our data. Variant chr17-43124076-G-A is described in ClinVar as Benign. ClinVar VariationId is 136537.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000177 (259/1461156) while in subpopulation AFR AF = 0.00646 (216/33456). AF 95% confidence interval is 0.00575. There are 1 homozygotes in GnomAdExome4. There are 107 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.21C>T	p.Arg7Arg	synonymous	Exon 2 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.21C>T	p.Arg7Arg	synonymous	Exon 2 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.21C>T	p.Arg7Arg	synonymous	Exon 2 of 24	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.21C>T	p.Arg7Arg	synonymous	Exon 2 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.21C>T	p.Arg7Arg	synonymous	Exon 2 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.21C>T	p.Arg7Arg	synonymous	Exon 2 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000442 AC: 111 AN: 251058 AF XY: 0.000332

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1461156 Hom.: 1 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 726946

African (AFR) AF: 0.00646 AC: 216 AN: 33456

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111436

Other (OTH) AF: 0.000447 AC: 27 AN: 60366

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74464

African (AFR) AF: 0.00546 AC: 227 AN: 41550

American (AMR) AF: 0.000392 AC: 6 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00174

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	BRCA1-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.63
DANN	Benign	0.86
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149402012; hg19: chr17-41276093; COSMIC: COSV58790612; COSMIC: COSV58790612;