17-43115744-C-T

Variant names:

• chr17-43115744-C-T
• rs80357498
• NM_007294.4:c.116G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001407694.1(BRCA1):​c.-142G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004823700: Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID:11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399)." 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_001407694.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 3.48
• Publications: 60 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004823700: Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399).; SCV000277193: Cells with p.C39Y are deficient in the control of centrosome number (Kais Z et al. Oncogene. 2012 Feb 9;31(6):799-804). Other studies have demonstrated abolishment and decreased activity of ubiquitin protein ligase function the BRCA1 RING finger in vitro (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). In addition, p.C39Y failed to reverse gamma radiation (IR) hypersensitivity in vivo (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9).; SCV000688318: Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, ubiquitin E3 ligase, haploid cell proliferation, centrosome duplication and yeast colony size assays (PMID: 11320250, 20103620, 21725363, 23161852, 25823446, 27272900, 30209399).; SCV000293476: Published functional studies demonstrate a damaging effect: defective ubiquitin ligase activity, homology directed repair activity, BARD1 binding, double-strand break repair, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Ruffner 2001, Ransburgh 2010, Millot 2011, Kais 2012, Towler 2013, Findlay 2018); SCV004222551: Functional studies report a reduction of E3 ubiquitin ligase activity, RING domain binding, resistance to ionizing radiation, and DNA repair ability (PMIDs: 11320250 (2001), 20103620 (2010), 25823446 (2015), and 33087888 (2021)).; SCV001583684: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11320250, 20103620, 21725363, 21922593, 23161852, 27272900).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43115744-C-T is Pathogenic according to our data. Variant chr17-43115744-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407694.1. 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.116G>A	p.Cys39Tyr	missense	Exon 3 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407694.1		c.-142G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001394623.1	A0A9Y1QQK3
	BRCA1	NM_001407695.1		c.-146G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 24	NP_001394624.1	P38398-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.116G>A	p.Cys39Tyr	missense	Exon 3 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.116G>A	p.Cys39Tyr	missense	Exon 3 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.116G>A	p.Cys39Tyr	missense	Exon 3 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (8)
4	-	-	not provided (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Breast neoplasm (1)
1	-	-	Malignant tumor of urinary bladder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		3.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.92
MutPred		1.0		Loss of methylation at K38 (P = 0.1129)
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs80357498; hg19: chr17-41267761;