rs80358163

Variant names:

• chr17-43104968-T-C
• rs80358163
• NM_007294.4:c.213-12A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43104968-T-C
• chr17-43104968-T-A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.213-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000296403: The inclusion of this intronic sequence alters the translation reading frame of the BRCA1 mRNA and is predicted to cause the synthesis of a truncated BRCA1 protein (PMID:23164213 (2012), 21735045 (2012), and 9805131 (1998))." and additional evidence is available in ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 intron
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic reviewed by expert panel P:33
• Conservation: PhyloP100: 0.312
• Publications: 26 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000296403: The inclusion of this intronic sequence alters the translation reading frame of the BRCA1 mRNA and is predicted to cause the synthesis of a truncated BRCA1 protein (PMID: 23164213 (2012), 21735045 (2012), and 9805131 (1998)).; SCV001548920: RT-PCR analysis on whole blood lymphocyte showed an 11 nucleotide insert at the intron 4/exon 6 boundary leading to a frameshift and truncated protein (Hoffman_1998_ 9805131).; SCV000683015: An RNA study has shown that this variant causes new splice acceptor that inserts 11 bp at the beginning of exon 6, resulting in frameshift and premature truncation within exon 6 (PMID: 9805131).; SCV000075739: Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9805131; internal data).; SCV000271314: "In vitro functional studies provide evidence that the c.213-12A>G variant introduces a cryptic splice site, causing an additional 11 nucleotides to be retained and leading to a frameshift, which alters the protein's amino acid sequence beginning at position 71 and leads to a premature termination codon 21 amino acids downstream." PMID:9827874; SCV000698920: The variant was reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Hoffmann_1998). At least one publication reports experimental evidence that this variant affects mRNA splicing by incorporation of 11 bases of intron 5 leading to a frameshift in the codon sequence (Hoffman_1998).; SCV000806910: "This variant has been shown by RT-PCR to alter normal splicing of intron 5 (Hoffman et al., 1998. PubMed ID: 9805131; Menéndez et al., 2012. PubMed ID: 21735045)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43104968-T-C is Pathogenic according to our data. Variant chr17-43104968-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 37450.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.213-12A>G		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.213-12A>G		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.213-12A>G		intron	N/A	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.213-12A>G		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.213-12A>G		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.213-12A>G		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000852 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (11)
10	-	-	not provided (10)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	BRCA1-related disorder (1)
1	-	-	Breast and/or ovarian cancer (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	-	-	not specified (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		0.31
PromoterAI		-0.0023	Neutral
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
Splicevardb		3.0
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -1
DS_AL_spliceai		0.68		Position offset: -12

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: rs80358163;

hg19: chr17-41256985;