chr17-43051063-C-T

Variant names:

• chr17-43051063-C-T
• rs80357112
• NM_007294.4:c.5332G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5332G>A​(p.Asp1778Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000076949: Experimental studies have shown that this missense change does not substantially affect BRCA1 protein function (PMID:20378548, 20516115, 25748678, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:22505045, 25724305, 30315757; Invitae).; SCV004829756: Functional studies suggest that the amino acid change may not have a substantial effect on the protein function (20378548, 20516115, 25748678, 30765603), but that this variant may disrupt the protein by causing alternate splicing (PMID:25724305, 31642931, 30315757).; SCV000186374: RNA assays have shown that this variant leads to skipping of exon 21 (coding exon 19) (Houdayer C et al. Hum Mutat 2012 Aug;33:1228-38; Ahlborn LB et al. Breast Cancer Res Treat. 2015 Apr;150:289-98; Minucci A et al. Clin Biochem 2019 Jan;63:54-58; Ambry internal data).; SCV006310892: RT-PCR demonstrated that the variant impacts splicing by skipping of exon 21 (PMID:25724305, 22505045). Minigene and gel electrophoresis assessment determined that the percent of reference (full-length) and aberrant transcript gel band intensities were 0 % / 100 %, respectively (PMID 25724305). An additional RT-PCR based study demonstrated that the variant impacts splicing by skipping of exon 21 (PMID:30315757).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1778E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:2
• Conservation: PhyloP100: 4.23
• Publications: 29 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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076949: Experimental studies have shown that this missense change does not substantially affect BRCA1 protein function (PMID: 20378548, 20516115, 25748678, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045, 25724305, 30315757; Invitae).; SCV004829756: Functional studies suggest that the amino acid change may not have a substantial effect on the protein function (20378548, 20516115, 25748678, 30765603), but that this variant may disrupt the protein by causing alternate splicing (PMID: 25724305, 31642931, 30315757).; SCV000186374: RNA assays have shown that this variant leads to skipping of exon 21 (coding exon 19) (Houdayer C et al. Hum Mutat 2012 Aug;33:1228-38; Ahlborn LB et al. Breast Cancer Res Treat. 2015 Apr;150:289-98; Minucci A et al. Clin Biochem 2019 Jan;63:54-58; Ambry internal data).; SCV006310892: RT-PCR demonstrated that the variant impacts splicing by skipping of exon 21 (PMID: 25724305, 22505045). Minigene and gel electrophoresis assessment determined that the percent of reference (full-length) and aberrant transcript gel band intensities were 0 % / 100 %, respectively (PMID 25724305). An additional RT-PCR based study demonstrated that the variant impacts splicing by skipping of exon 21 (PMID: 30315757).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 79 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43051062-CCT-ATGTTG is described in ClinVar as Pathogenic. ClinVar VariationId is 236263.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 17-43051063-C-T is Pathogenic according to our data. Variant chr17-43051063-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55530.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.5332G>A	p.Asp1778Asn	missense splice_region	Exon 20 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5398G>A	p.Asp1800Asn	missense splice_region	Exon 21 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5398G>A	p.Asp1800Asn	missense splice_region	Exon 21 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.5332G>A	p.Asp1778Asn	missense splice_region	Exon 20 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5395G>A	p.Asp1799Asn	missense splice_region	Exon 21 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5332G>A	p.Asp1778Asn	missense splice_region	Exon 20 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	BRCA1-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.58
Sift	Benign	0.057	T
Sift4G	Benign	0.13	T
Polyphen		0.041	B
Vest4		0.51
MVP		0.86
MPC		0.25
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.59
gMVP		0.35
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.12		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: rs80357112; hg19: chr17-41203080;