chr17-43067610-G-A

Variant names:

• chr17-43067610-G-A
• rs80357034
• NM_007294.4:c.5072C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5072C>T​(p.Thr1691Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: "SCV000076775: Experimental studies have shown that this missense change affects BRCA1 function (PMID:20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:25724305, 31843900).; SCV000568401: Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID:20516115, 35665744, 32546644); SCV000605900: Functional evidence suggests that this variant may impact protein function (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30209399 (2018), 30765603 (2019), and 31843900 (2019)).; SCV000608092: One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69).; SCV004742153: Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1691S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2
• Conservation: PhyloP100: 6.01
• Publications: 51 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076775: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900).; SCV000568401: Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); SCV000605900: Functional evidence suggests that this variant may impact protein function (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30209399 (2018), 30765603 (2019), and 31843900 (2019)).; SCV000608092: One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69).; SCV004742153: Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644).
• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 75 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 chr17-43067610-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 17-43067610-G-A is Pathogenic according to our data. Variant chr17-43067610-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37628.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.5072C>T	p.Thr1691Ile	missense splice_region	Exon 16 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5138C>T	p.Thr1713Ile	missense splice_region	Exon 17 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5138C>T	p.Thr1713Ile	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.5072C>T	p.Thr1691Ile	missense splice_region	Exon 16 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5135C>T	p.Thr1712Ile	missense splice_region	Exon 17 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5072C>T	p.Thr1691Ile	missense splice_region	Exon 16 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
3	-	-	not provided (3)
1	-	-	BRCA1-related disorder (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.96
MPC		0.18
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.76
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: -2

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

Other links and lift over

dbSNP: rs80357034; hg19: chr17-41219627;