17-43067608-C-T

Variant names:

• chr17-43067608-C-T
• rs80187739
• NM_007294.4:c.5074G>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.5074G>A​(p.Asp1692Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003843144: An in vitro study demonstrated that this variant leads to multiple aberrant transcripts, including one causing exon 17 skipping and another causing activation of a cryptic splice donor site that leads to an in-frame retention of 153 bp of intron 17 (PMID:25724305).; SCV000273244: One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222).; SCV000904696: Functional RNA studies have shown that this variant causes a splicing defect leading to skipping of exon 16 or in-frame retention of part of intron 15 (PMID:25724305).; SCV000322096: Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay et al., 2018); SCV001585898: Experimental studies have shown that this missense change affects BRCA1 function (PMID:25748678, 30209399).; SCV003923014: This variant results in loss of function (Findlay_2018).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1692G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 4.72
• Publications: 66 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: SCV003843144: An in vitro study demonstrated that this variant leads to multiple aberrant transcripts, including one causing exon 17 skipping and another causing activation of a cryptic splice donor site that leads to an in-frame retention of 153 bp of intron 17 (PMID: 25724305).; SCV000273244: One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM. Nature. 2018 10;562(7726):217-222).; SCV000904696: Functional RNA studies have shown that this variant causes a splicing defect leading to skipping of exon 16 or in-frame retention of part of intron 15 (PMID: 25724305).; SCV000322096: Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay et al., 2018); SCV001585898: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25748678, 30209399).; SCV003923014: This variant results in loss of function (Findlay_2018).
• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 72 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 chr17-43063950-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 864924.
• 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 17-43067608-C-T is Pathogenic according to our data. Variant chr17-43067608-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.5074G>A	p.Asp1692Asn	missense splice_region	Exon 16 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5140G>A	p.Asp1714Asn	missense splice_region	Exon 17 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5140G>A	p.Asp1714Asn	missense splice_region	Exon 17 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.5074G>A	p.Asp1692Asn	missense splice_region	Exon 16 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5137G>A	p.Asp1713Asn	missense splice_region	Exon 17 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5074G>A	p.Asp1692Asn	missense splice_region	Exon 16 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.74	P
Vest4		0.72
MVP		0.90
MPC		0.080
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.73
gMVP		0.61
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 0

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

Other links and lift over

dbSNP: rs80187739; hg19: chr17-41219625; COSMIC: COSV58787854;