chr17-43051104-A-G

Variant names:

• chr17-43051104-A-G
• rs80357281
• NM_007294.4:c.5291T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5291T>C​(p.Leu1764Pro) variant causes a missense change. 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: "SCV004829741: Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and additional assays (PMID:30257991, 30209399, 29884841, 27272900, 23867111, 20516115, 20378548, 17308087)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1764Q) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1
• Conservation: PhyloP100: 5.03
• Publications: 38 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: SCV004829741: Functional studies have reported that this variant impacts BRCA1 function in homology-directed DNA repair, transcription activation, haploid cell proliferation and additional assays (PMID: 30257991, 30209399, 29884841, 27272900, 23867111, 20516115, 20378548, 17308087).; SCV000607979: Functional studies including c-DNA complementation, homologous recombination, yeast-based assays, nuclear localization and solubility assays, and transcription activation assays have all demonstrated deficient function (Carvalho MA et al. Cancer Res. 2007 Feb; 67(4):1494-501; Bouwman P et al. Cancer Discov. 2013 Oct; 3(10):1142-55; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Woods NT et al. NPJ Genom Med 2016 Mar;1; Petitalot A et al. Mol. Cancer Res. 2019 01;17(1):54-69). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222).; SCV000699234: Multiple functional studies have been performed that support these predictions. The variant of interest has been indicated to cause fold destabilization.; SCV001578892: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 20378548, 20516115, 23867111, 27272900, 30209399).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 82 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 17-43051104-A-G is Pathogenic according to our data. Variant chr17-43051104-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55510.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.5291T>C	p.Leu1764Pro	missense	Exon 20 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5357T>C	p.Leu1786Pro	missense	Exon 21 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5357T>C	p.Leu1786Pro	missense	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.5291T>C	p.Leu1764Pro	missense	Exon 20 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5354T>C	p.Leu1785Pro	missense	Exon 21 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5291T>C	p.Leu1764Pro	missense	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
5	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (6)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs80357281; hg19: chr17-41203121;