rs80357446

Variant names:

• chr17-43115729-C-A
• rs80357446
• NM_007294.4:c.131G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43115729-C-A
• chr17-43115729-C-G
• chr17-43115729-C-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001407841.1(BRCA1):​c.-8+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV003927211: Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID:20103620, 16403807, 23161852, 21725363, 27272900)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_001407841.1 splice_donor, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:25 U:1
• Conservation: PhyloP100: 3.48
• Publications: 48 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 4, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003927211: Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID: 20103620, 16403807, 23161852, 21725363, 27272900).; SCV004823698: Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064).; SCV000217719: Multiple functional studies have shown that this alteration is deleterious including a centrosome amplification assay, a homology directed repair assay, a single stranded annealing assay and a high throughput cell survival assay (Kais Z et al. Oncogene. 2012 Feb;31:799-804; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature, 2018 Sep;).; SCV000682947: Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064).; SCV000296760: This variant is also known as c.250G>T in the literature and it was shown to disrupt normal protein function by a yeast two-hybrid E3 Ub-ligase activity assay, a homology directed recombination assay, a BARD1 binding assay and a centrosome amplification assay (PMID: 20103620, 21725363).; SCV000512277: Published functional studies demonstrate a damaging effect: disrupted homology-directed repair and BARD1 binding, and loss of E3 ubiquitin ligase activity and centrosome amplification (Morris 2006, Ransburgh 2010, Kais 2012, Starita 2015, Findlay 2018);; SCV000918696: Multiple functional studies found that the variant significantly impacts proper BRCA1 protein function (Kais_2012, Morris_2006,Ransburgh_2010, Towler_2013, and Thouvenot_2016).; SCV001591919: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 20103620, 21725363, 22843421, 23161852, 27272900).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43115729-C-A is Pathogenic according to our data. Variant chr17-43115729-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 54200.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407841.1. 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.131G>T	p.Cys44Phe	missense	Exon 3 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.131G>T	p.Cys44Phe	missense	Exon 3 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.131G>T	p.Cys44Phe	missense	Exon 3 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.131G>T	p.Cys44Phe	missense	Exon 3 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.131G>T	p.Cys44Phe	missense	Exon 3 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.131G>T	p.Cys44Phe	missense	Exon 3 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461168 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726864

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111648

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (10)
7	-	-	not provided (7)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S (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	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		3.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.98		Loss of disorder (P = 0.0952)
MVP		1.0
MPC		0.15
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80357446; hg19: chr17-41267746;