rs4986854

Variant names:

• chr17-43071031-A-G
• rs4986854
• NM_007294.4:c.4883T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-43071031-A-G
• chr17-43071031-A-T
• chr17-43071031-A-C

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.4883T>C​(p.Met1628Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,614,148 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. M1628V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (9 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:30 O:1
• Conservation: PhyloP100: -0.667
• Publications: 76 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015231997).
• BP6: Variant 17-43071031-A-G is Benign according to our data. Variant chr17-43071031-A-G is described in ClinVar as Benign. ClinVar VariationId is 41828.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0011 (168/152258) while in subpopulation EAS AF = 0.00887 (46/5188). AF 95% confidence interval is 0.00683. There are 2 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.4883T>C	p.Met1628Thr	missense	Exon 15 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4949T>C	p.Met1650Thr	missense	Exon 16 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4949T>C	p.Met1650Thr	missense	Exon 16 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.4883T>C	p.Met1628Thr	missense	Exon 15 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4946T>C	p.Met1649Thr	missense	Exon 16 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4883T>C	p.Met1628Thr	missense	Exon 15 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00147 AC: 370 AN: 251392 AF XY: 0.00127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00430

Gnomad FIN exome AF: 0.00739

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000945 AC: 1382 AN: 1461890 Hom.: 9 Cov.: 31 AF XY: 0.000949 AC XY: 690 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26136

East Asian (EAS) AF: 0.0128 AC: 509 AN: 39698

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.00777 AC: 415 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 204 AN: 1112012

Other (OTH) AF: 0.00113 AC: 68 AN: 60396

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00887 AC: 46 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

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

Alfa AF: 0.000861 Hom.: 5

Bravo AF: 0.000351

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	9	Breast-ovarian cancer, familial, susceptibility to, 1 (10)
-	-	6	not specified (7)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	not provided (3)
-	-	1	BRCA1-related disorder (1)
-	-	1	Breast neoplasm (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)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	0.056
DANN	Benign	0.18
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.67
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.49
Sift	Benign	0.56	T
Sift4G	Benign	0.29	T
Polyphen		0.039	B
Vest4		0.26
MVP		0.39
MPC		0.094
ClinPred		0.0046	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.18
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4986854; hg19: chr17-41223048;