rs28897673

Variant names:

• chr17-43104249-T-C
• rs28897673
• NM_007294.4:c.314A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43104249-T-C
• chr17-43104249-T-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_001407959.1(BRCA1):​c.-68A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,610,448 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: BRCA1 NM_001407959.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 1.32
• Publications: 34 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3143799).
• BP6: Variant 17-43104249-T-C is Benign according to our data. Variant chr17-43104249-T-C is described in ClinVar as Benign. ClinVar VariationId is 54780.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407959.1. 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.314A>G	p.Tyr105Cys	missense	Exon 6 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407959.1		c.-68A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 20	NP_001394888.1
	BRCA1	NM_001407960.1		c.-68A>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 21	NP_001394889.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.314A>G	p.Tyr105Cys	missense	Exon 6 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.314A>G	p.Tyr105Cys	missense	Exon 6 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.314A>G	p.Tyr105Cys	missense	Exon 6 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000877 AC: 22 AN: 250980 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1458246 Hom.: 1 Cov.: 33 AF XY: 0.000179 AC XY: 130 AN XY: 725684

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.000112 AC: 5 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.000239 AC: 265 AN: 1108972

Other (OTH) AF: 0.0000995 AC: 6 AN: 60298

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
-	-	6	not specified (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Breast neoplasm (1)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Inherited ovarian cancer (without breast cancer) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.63
Sift	Benign	0.13	T
Sift4G	Uncertain	0.039	D
Polyphen		0.43	B
Vest4		0.58
MVP		0.97
MPC		0.47
ClinPred		0.12	T
GERP RS		4.2
Varity_R		0.086
gMVP		0.40
Mutation Taster		=72/28	polymorphism

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: rs28897673; hg19: chr17-41256266;