17-43045767-G-A

Variant names:

• chr17-43045767-G-A
• rs41293465
• NM_007294.4:c.5503C>T
• BRCA1 p.Arg1835*

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5503C>T​(p.Arg1835*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,874 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: "SCV000210227: Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1835R) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:55
• Conservation: PhyloP100: 0.950
• Publications: 70 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 86 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000210227: Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018).; SCV000296284: Functional studies found that this variant was damaging to protein function (PMIDs: 29280214 (2018) and 30209399 (2018)).; SCV002070456: Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798).; SCV004034290: Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798).; SCV004817536: "This variant has been reported to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399)."; SCV005044822: The experimental studies have shown that this premature translational stop signal affects BRCA1 function Ye Q et al 2001.; SCV000186917: One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay, 2018).; SCV000537638: This variant has been reported to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399).; SCV000077033: Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 11739404).; SCV004848012: in vitro functional studies provide some evidence that this truncation may impact protein function (Ye 2001).; SCV000591636: two functional studies using the yeast two-hybrid screen and glutathione-S-transferase (GST) pull-down assay, determined that the variant abolished interaction of BRCA1 with two proteins: Acetyl Coenzyme A (CoA) Carboxylase and PABP (Dizin 2006, Magnard 2002).
• PP5: Variant 17-43045767-G-A is Pathogenic according to our data. Variant chr17-43045767-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55601.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.5503C>T	p.Arg1835*	stop_gained	Exon 23 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5569C>T	p.Arg1857*	stop_gained	Exon 24 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5569C>T	p.Arg1857*	stop_gained	Exon 24 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.5503C>T	p.Arg1835*	stop_gained	Exon 23 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5566C>T	p.Arg1856*	stop_gained	Exon 24 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5503C>T	p.Arg1835*	stop_gained	Exon 23 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251278 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000996 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
19	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (19)
15	-	-	not provided (15)
5	-	-	Hereditary breast ovarian cancer syndrome (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	Inherited breast cancer and ovarian cancer (3)
2	-	-	Breast and/or ovarian cancer (2)
1	-	-	Breast carcinoma (1)
1	-	-	Breast neoplasm (1)
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)
1	-	-	Gastric cancer (1)
1	-	-	Lung cancer;C0346153:Familial cancer of breast;C0919267:Ovarian neoplasm (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.59	D
PhyloP100		0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41293465;

hg19: chr17-41197784;

COSMIC: COSV58789996;