rs397509222

Variant names:

• chr17-43063951-T-A
• rs397509222
• NM_007294.4:c.5075A>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43063951-T-A
• chr17-43063951-T-C
• chr17-43063951-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5075A>T variant in BRCA1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1692 (p.Asp1692Val). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant has a SpliceAI score of 0.32, predicting an impact on splicing (score threshold ≥0.2) (PP3 met). Missense variant predicted to alter splicing, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit function similar to pathogenic control variants (PMID:30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 15.2 (based on Family History LR=15.2), within the thresholds for moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID, 3185305). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003216/MONDO:0700268/092

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407581.1 missense, splice_region
• Scores: Splicing: ADA: 0.7225
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:6
• Conservation: PhyloP100: 4.92
• Publications: 14 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):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407581.1. 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.5075A>T	p.Asp1692Val	missense splice_region	Exon 17 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5141A>T	p.Asp1714Val	missense splice_region	Exon 18 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5141A>T	p.Asp1714Val	missense splice_region	Exon 18 of 24	NP_001394511.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5075A>T	p.Asp1692Val	missense splice_region	Exon 17 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5138A>T	p.Asp1713Val	missense splice_region	Exon 18 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5075A>T	p.Asp1692Val	missense splice_region	Exon 17 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	2	-	not provided (2)
1	-	-	BRCA1-related cancer predisposition (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.011	B
Vest4		0.83
MVP		0.96
MPC		0.19
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.80
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.54
Splicevardb		3.0
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs397509222; hg19: chr17-41215968; COSMIC: COSV107367484;