17-43115729-C-T

Position:

• chr17-43115729-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001407841.1(BRCA1):​c.-8+1G>A variant causes a splice donor, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407841.1 splice_donor, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1 O:1
• Conservation: PhyloP100: 3.48

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43115729-C-T is Pathogenic according to our data. Variant chr17-43115729-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54199.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115729-C-T is described in Lovd as [Pathogenic]. Variant chr17-43115729-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.131G>A	p.Cys44Tyr	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.131G>A	p.Cys44Tyr	missense_variant	3/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 20, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 24, 2008	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 07, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/282214 chr). Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2023	Published functional studies demonstrate a damaging effect: reduced cellular proliferation, nuclear localization, and E3 ubiquitin ligase activity, as well as an inability to form a functional heterodimer with BARD1 (Brzovic et al., 2003; Morris et al., 2006; Millot et al., 2011; Starita et al., 2015); in addition, colony size, spot formation, and yeast localization assays of this variant also demonstrated a pathogenic effect (Thouvenot et al., 2016); A multifactorial model strongly predicted this variant to be deleterious (Lindor et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, including an individual with early-onset, triple negative disease and family history of bilateral breast cancer (Sweet et al., 2010; Sun et al., 2017); Also known as 250G>A; This variant is associated with the following publications: (PMID: 16403807, 12732733, 30209399, 24489791, 16267036, 24312913, 25823446, 27272900, 28724667, 30702160, 31825140, 33087888, 29446198, 21922593, 21990134, 8944023, 20104584, 24389207, 19543972) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The p.C44Y variant (also known as c.131G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 131. The cysteine at codon 44 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, along with another alteration, p.C44S, at the same position, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat., 2012 Jan;33:8-21). This alteration was shown to disrupt the function of the protein in multiple functional studies using different assays (Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Starita LM et al. Genetics, 2015 Jun;200:413-22; Thouvenot P et al. PLoS Genet., 2016 Jun;12:e1006096). In addition, a recent 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 44 of the BRCA1 protein (p.Cys44Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 19543972, 27083775). ClinVar contains an entry for this variant (Variation ID: 54199). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 21922593, 27272900). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21990134, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;T;T;T;T;T;D;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;N;N;D;D;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 0.61, 1.0	.;D;.;.;P;.;D;.;.;.;.;.;.
Vest4		0.94
MutPred		0.99		Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);
MVP		1.0
MPC		0.17
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357446; hg19: chr17-41267746;