17-43082453-A-G

Variant names:

• chr17-43082453-A-G
• rs1060915
• NM_007294.4:c.4308T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_007294.4(BRCA1):​c.4308T>C​(p.Ser1436Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,730 control chromosomes in the GnomAD database, including 92,806 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. S1436S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7439 hom., cov: 32)
  • Exomes 𝑓: 0.34 (85367 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:29 O:2
• Conservation: PhyloP100: 0.103
• Publications: 144 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.058).
• BP6: Variant 17-43082453-A-G is Benign according to our data. Variant chr17-43082453-A-G is described in ClinVar as Benign. ClinVar VariationId is 125703.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4308T>C	p.Ser1436Ser	synonymous	Exon 12 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4308T>C	p.Ser1436Ser	synonymous	Exon 12 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4308T>C	p.Ser1436Ser	synonymous	Exon 12 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.4308T>C	p.Ser1436Ser	synonymous	Exon 12 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4308T>C	p.Ser1436Ser	synonymous	Exon 12 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4308T>C	p.Ser1436Ser	synonymous	Exon 12 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45723 AN: 151996 Hom.: 7437 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.349 AC: 87615 AN: 251392 AF XY: 0.358

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.338 AC: 493418 AN: 1461616 Hom.: 85367 Cov.: 41 AF XY: 0.343 AC XY: 249269 AN XY: 727112

African (AFR) AF: 0.175 AC: 5856 AN: 33472

American (AMR) AF: 0.315 AC: 14086 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 9365 AN: 26130

East Asian (EAS) AF: 0.353 AC: 13997 AN: 39694

South Asian (SAS) AF: 0.499 AC: 43012 AN: 86252

European-Finnish (FIN) AF: 0.396 AC: 21169 AN: 53416

Middle Eastern (MID) AF: 0.368 AC: 2125 AN: 5768

European-Non Finnish (NFE) AF: 0.327 AC: 363636 AN: 1111776

Other (OTH) AF: 0.334 AC: 20172 AN: 60388

GnomAD4 genome AF: 0.301 AC: 45729 AN: 152114 Hom.: 7439 Cov.: 32 AF XY: 0.307 AC XY: 22841 AN XY: 74338

African (AFR) AF: 0.180 AC: 7486 AN: 41526

American (AMR) AF: 0.320 AC: 4889 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1223 AN: 3470

East Asian (EAS) AF: 0.369 AC: 1908 AN: 5176

South Asian (SAS) AF: 0.492 AC: 2370 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4265 AN: 10562

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22544 AN: 67970

Other (OTH) AF: 0.324 AC: 684 AN: 2110

Alfa AF: 0.314 Hom.: 17417

Bravo AF: 0.284

Asia WGS AF: 0.406 AC: 1410 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.333

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	Breast-ovarian cancer, familial, susceptibility to, 1 (11)
-	-	8	not specified (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Familial cancer of breast (2)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		0.10
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: rs1060915; hg19: chr17-41234470; COSMIC: COSV58783806; COSMIC: COSV58783806;