17-43063903-G-T

Variant names:

• chr17-43063903-G-T
• rs28897696
• NM_007294.4:c.5123C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5123C>A​(p.Ala1708Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000296313: Functional studies indicate that this variant has a damaging effect on BRCA1 protein structure and function and may result in aberrant BRCA1 mRNA splicing (PMIDs: 20215541 (2010), 19404736 (2010), 20516115 (2010), 18036263 (2007), 17305420 (2007), 12400015 (2002), 11157798 (2001))." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1708G) has been classified as Likely pathogenic. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:39
• Conservation: PhyloP100: 6.18
• Publications: 228 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000296313: Functional studies indicate that this variant has a damaging effect on BRCA1 protein structure and function and may result in aberrant BRCA1 mRNA splicing (PMIDs: 20215541 (2010), 19404736 (2010), 20516115 (2010), 18036263 (2007), 17305420 (2007), 12400015 (2002), 11157798 (2001)).; SCV001473240: Functional assays have confirmed this variant causes loss of function (Findlay 2018, Sanz 2010).; SCV000186886: Multiple functional studies have classified this alteration as deleterious (Findlay GM et al. Nature 2018 10;562(7726):217-222; Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lovelock PK et al. J. Med. Genet. 2006 Jan;43:74-83).; SCV000537686: Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882).; SCV000076815: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11157798, 15923272, 17305420, 19770520, 20516115, 25748678).; SCV000605743: In vitro functional studies provide some evidence that the p.Ala1729Glu variant may cause skipping of exon 18 (Millevoi 2010, Sanz 2010).; SCV000699205: A functional study demonstrated the variant to result in inappropriate skipping of the entire exon 18, to reduce structural stability, phosphopeptide binding and transcription activity further supporting a deleterious impact.; SCV000806966: Functional studies have also reported that this variant impacts protein stability (Rowling et al. 2010. PubMed ID: 20378548) and results in skipping of exon 18 (Millevoi et al. 2010. PubMed ID: 19404736).; SCV004817587: Functional studies have reported this variant impacts BRCA1 function in mammalian transcription activation assays (PMID: 15923272, 11157798, 17305420), complementation of BRCA1-deficient embryonic stem cells (PMID: 19770520, 23867111), a haploid cell proliferation assay (PMID: 30209399) and homology-directed repair and chromosome aberration assays (PMID: 34855882).
• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 64 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063903-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 867673.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 17-43063903-G-T is Pathogenic according to our data. Variant chr17-43063903-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55407.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.5123C>A	p.Ala1708Glu	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5189C>A	p.Ala1730Glu	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5189C>A	p.Ala1730Glu	missense	Exon 18 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.5123C>A	p.Ala1708Glu	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5186C>A	p.Ala1729Glu	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5123C>A	p.Ala1708Glu	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251312 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.000122 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (16)
8	-	-	not provided (8)
6	-	-	Hereditary breast ovarian cancer syndrome (6)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	BRCA1-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast neoplasm (1)
1	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.92
MVP		0.97
MPC		0.47
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.15		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: rs28897696; hg19: chr17-41215920; COSMIC: COSV58803602;