17-43076488-C-T

Variant names:

• chr17-43076488-C-T
• rs80357389
• NM_007294.4:c.4484G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.4484G>A​(p.Arg1495Lys) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000213365: RNA studies demonstrated that this mutation leads to skipping of coding exon 12, which results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1495T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:4
• Conservation: PhyloP100: 3.88
• Publications: 88 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000213365: RNA studies demonstrated that this mutation leads to skipping of coding exon 12, which results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38).; SCV000905202: RNA studies have shown that this variant resulted in the out-of-frame skipping of exon 13 and that this variant transcript is not stably expressed based on an allelic imbalance assay on patient-derived RNA (PMID: 19471317, 22505045, 31143303).; SCV000568404: RNA analyses demonstrate that this variant leads to skipping of exon 14, resulting in premature protein truncation, subject to nonsense-mediated decay (Houdayer et al., 2012; Wangensteen et al., 2019); SCV000887697: "In vitro studies have shown that this variant causes a severe and complete splicing defect resulting in exon 13 (legacy exon 14) skipping." PMID:19471317 (2009), 22505045 (2012), 31143303 (2019); SCV001590561: Studies have shown that this missense change results in skipping of exon 13 (also called exon 14 in published literature), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19471317, 22505045; internal data).; SCV002598861: At least two publications have provided experimental evidence to demonstrate that this variant does indeed affect mRNA splicing, indicating that it results in the skipping of exon 13 which produces a frameshift, ultimately leading to a premature stop codon (e.g. Houdayer_2012, Wangensteen_2019).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43076488-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 245697.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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43076488-C-T is Pathogenic according to our data. Variant chr17-43076488-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37597.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.4484G>A	p.Arg1495Lys	missense splice_region	Exon 13 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4550G>A	p.Arg1517Lys	missense splice_region	Exon 14 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4550G>A	p.Arg1517Lys	missense splice_region	Exon 14 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.4484G>A	p.Arg1495Lys	missense splice_region	Exon 13 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4547G>A	p.Arg1516Lys	missense splice_region	Exon 14 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4484G>A	p.Arg1495Lys	missense splice_region	Exon 13 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: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
2	2	-	not provided (4)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial cancer of breast (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.95	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.020	D
Sift4G	Benign	0.52	T
Polyphen		0.17	B
Vest4		0.52
MVP		0.86
MPC		0.091
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.17
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.51		Position offset: 0

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

Other links and lift over

dbSNP: rs80357389; hg19: chr17-41228505;