rs876658362

Variant names:

• chr17-43115728-G-A
• rs876658362
• NM_007294.4:c.132C>T
• BRCA1 p.Cys44Cys

Your query was ambiguous. Multiple possible variants found:

• chr17-43115728-G-A
• chr17-43115728-G-C
• chr17-43115728-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePS1PS3PM2PP5_Strong

The NM_001407841.1(BRCA1):c.-8+2C>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. Note: NM_001407841.1 is not a MANE Select or MANE Plus Clinical transcript for BRCA1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. This is a canonical splice-site variant (loss-of-function). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000273476: "One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222)."" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407841.1 splice_donor, intron
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.40
• Publications: 8 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 points.

• PVS1: Non-NMD splice frameshift: disease mechanism, small exon — moderate (PVS1 downgraded to PM); Splice donor variant predicted to cause a frameshift; NMD not predicted. Loss of function is a known disease mechanism, but the exon is small.
• PS1: Splice site has a more-destructive ClinVar pathogenic — strong (PS1); A more pathogenic splice-site variant at the same position has been reported in ClinVar.
• PS3: Well-established functional study supports damaging effect (PS3); SCV000273476: "One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222)."; SCV004361133: "A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay and decreases RNA transcript abundance (PMID: 30209399)."; SCV001133483: RNA studies indicate this variant causes aberrant splicing and alters the reading frame of the BRCA1 mRNA, resulting in disrupted protein synthesis (PMIDs: 35087763 (2021), 24667779 (2014)). In addition, saturation genome editing assays measuring DNA repair-dependent cell survival characterized this variant as being non-functional (PMIDs: 32803532 (2020), 30209399 (2018)).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001407841.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.132C>T	p.Cys44Cys	splice_region synonymous	Exon 3 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407841.1		c.-8+2C>T		splice_donor intron	N/A	NP_001394770.1
	BRCA1	NM_001407581.1		c.132C>T	p.Cys44Cys	splice_region synonymous	Exon 3 of 24	NP_001394510.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.132C>T	p.Cys44Cys	splice_region synonymous	Exon 3 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.132C>T	p.Cys44Cys	splice_region synonymous	Exon 3 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.132C>T	p.Cys44Cys	splice_region synonymous	Exon 3 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Benign	0.93
PhyloP100		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
Splicevardb		3.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: 2
DS_DL_spliceai		0.33		Position offset: -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: rs876658362;

hg19: chr17-41267745;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar