17-43092412-C-T

Variant names:

• chr17-43092412-C-T
• rs4986852
• NM_007294.4:c.3119G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.3119G>A​(p.Ser1040Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,846 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1040G) has been classified as Likely benign. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 32)
  • Exomes 𝑓: 0.020 (318 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:40 O:1
• Conservation: PhyloP100: -0.0250
• Publications: 122 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005789846).
• BP6: Variant 17-43092412-C-T is Benign according to our data. Variant chr17-43092412-C-T is described in ClinVar as Benign. ClinVar VariationId is 17670.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2177/152184) while in subpopulation NFE AF = 0.0215 (1464/67996). AF 95% confidence interval is 0.0206. There are 20 homozygotes in GnomAd4. There are 966 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

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.3119G>A	p.Ser1040Asn	missense	Exon 10 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.3119G>A	p.Ser1040Asn	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.3119G>A	p.Ser1040Asn	missense	Exon 10 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.3119G>A	p.Ser1040Asn	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.3119G>A	p.Ser1040Asn	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.3119G>A	p.Ser1040Asn	missense	Exon 10 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2178 AN: 152066 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0132 AC: 3302 AN: 251032 AF XY: 0.0134

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0198 AC: 28896 AN: 1461662 Hom.: 318 Cov.: 41 AF XY: 0.0195 AC XY: 14177 AN XY: 727116

African (AFR) AF: 0.00412 AC: 138 AN: 33480

American (AMR) AF: 0.0112 AC: 502 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 506 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00595 AC: 513 AN: 86254

European-Finnish (FIN) AF: 0.00375 AC: 200 AN: 53276

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5768

European-Non Finnish (NFE) AF: 0.0233 AC: 25934 AN: 1111952

Other (OTH) AF: 0.0169 AC: 1021 AN: 60392

GnomAD4 genome AF: 0.0143 AC: 2177 AN: 152184 Hom.: 20 Cov.: 32 AF XY: 0.0130 AC XY: 966 AN XY: 74424

African (AFR) AF: 0.00453 AC: 188 AN: 41524

American (AMR) AF: 0.0174 AC: 266 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3470

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

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4822

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10596

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1464 AN: 67996

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0192 Hom.: 143

Bravo AF: 0.0159

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0219 AC: 188

ExAC AF: 0.0132 AC: 1598

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0238

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	12	Breast-ovarian cancer, familial, susceptibility to, 1 (14)
-	-	11	not specified (12)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	1	Familial cancer of breast (1)
-	-	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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.025
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.084	T
Sift4G	Benign	0.066	T
Polyphen		0.97	D
Vest4		0.21
MPC		0.13
ClinPred		0.0054	T
GERP RS		2.0
Varity_R		0.053
gMVP		0.12
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs4986852; hg19: chr17-41244429; COSMIC: COSV58791858; COSMIC: COSV58791858;