chr17-43063368-T-C

Variant names:

• chr17-43063368-T-C
• rs56195342
• NM_007294.4:c.5158A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.5158A>G​(p.Thr1720Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,611,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T1720S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:19
• Conservation: PhyloP100: 0.492
• Publications: 35 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 -10 ACMG points.

• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 76 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.065047204).
• BP6: Variant 17-43063368-T-C is Benign according to our data. Variant chr17-43063368-T-C is described in ClinVar as Benign. ClinVar VariationId is 55438.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5158A>G	p.Thr1720Ala	missense	Exon 18 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5224A>G	p.Thr1742Ala	missense	Exon 19 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5224A>G	p.Thr1742Ala	missense	Exon 19 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.5158A>G	p.Thr1720Ala	missense	Exon 18 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5221A>G	p.Thr1741Ala	missense	Exon 19 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5158A>G	p.Thr1720Ala	missense	Exon 18 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 250984 AF XY: 0.000155

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1459460 Hom.: 0 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 726278

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.000917 AC: 41 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000123 AC: 136 AN: 1110024

Other (OTH) AF: 0.000116 AC: 7 AN: 60332

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000954 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	5	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
-	-	6	not specified (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	BRCA1-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.49
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.27	T
Sift4G	Benign	0.094	T
Polyphen		0.021	B
Vest4		0.57
MVP		0.79
MPC		0.20
ClinPred		0.031	T
GERP RS		3.2
Varity_R		0.27
gMVP		0.27
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		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: rs56195342; hg19: chr17-41215385; COSMIC: COSV100524555;