17-43106486-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):c.182G>A(p.Cys61Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,452,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:1
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 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 chr17-43106487-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17661.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43106486-C-T is Pathogenic according to our data. Variant chr17-43106486-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106486-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.182G>A	p.Cys61Tyr	missense_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.182G>A	p.Cys61Tyr	missense_variant	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452504 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:1 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 06, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Dec 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 61 of the BRCA1 protein (p.Cys61Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18159056, 22752604, 25428789, 26287763, 28664506). ClinVar contains an entry for this variant (Variation ID: 54364). 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: 22843421, 25823446, 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Cys61 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7894493, 9525870, 11278247, 19594371, 19770520, 22172724). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2021	Variant summary: BRCA1 c.182G>A (p.Cys61Tyr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.182G>A has been reported in the literature in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in loss of homology directed repair (HDR) activity. Three clinical diagnostic laboratories, one research submitter, and one consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: impaired BARD1 binding and E3-auto-ubiquitination activity, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Starita et al., 2015; Findlay et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 301G>A; This variant is associated with the following publications: (PMID: 15235020, 20215423, 28664506, 26287763, 23867111, 23161852, 18159056, 22752604, 29446198, 25428789, 32741062, 33087888, 8944023, 24389207, 20104584, 30209399, 25823446) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Cys61Tyr variant was identified in dbSNP (ID: rs80357093) “With pathogenic allele”, HGMD, and the BIC database (6X with unknown clinical importance). The p.Cys61 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys61Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Abkevich (2004) notes that p.Cys61 is a C3HC4 RING finger canonical residue, and that the p.Cys61Tyr variant is classified as deleterious by Myriad. In addition, another variant at this amino acid position, p.Cys61Gly, has been listed in public databases as a pathogenic variant, including 45X in UMD (as a "causal" variant) and 239X in the BIC database (as a variant with clinical importance). This p.Cys61Gly variant has also been characterized as deleterious by different functional assays, including evaluations of the p.Cys61Gly variant on double strand break repair and protein expression (Li 2010, Towler 2013, Bouwman 2013), suggesting that this residue is functionally important and the p.Cys61Tyr variant may also impact protein function. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2022	The p.C61Y pathogenic mutation (also known as c.182G>A), located in coding exon 3 of the BRCA1 gene, results from a G to A substitution at nucleotide position 182. The cysteine at codon 61 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9; Pal T et al. Cancer. 2015 Dec;121(23):4173-80; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165:687-697). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In one high throughput functional study, this variant was shown to impair both BARD1 binding activity and E3 Ubiquitin ligase function of the protein (Starita LM et al. Genetics. 2015 Jun;200:413-22). Another 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;562:217-222). Based on internal structural assessment, this alteration disrupts one of the Zn-binding sites of the BRCA1 RING domain (Ambry internal data; Brzovic PS et al. Nat. Struct. Biol., 2001 Oct;8:833-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 07, 2021	This missense variant replaces cysteine with tyrosine at codon 61 of the BRCA1 protein. The impacted reference cysteine is one of the eight conserved cysteine/histidine for the zinc finger motif in the RING domain (PMID: 11526114). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in ubiquitin E3 ligase, BARD1 binding and haploid human cell proliferation assays (PMID: 25823446, 30209399). This variant has been reported in at least seven individuals affected with breast cancer (PMID: 18159056, 22752604, 25428789, 26287763, 28664506). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.52	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N;N;N;D;N;N;D;N;N;.;N;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;.;T;D;.;D;D;.;.
Polyphen		1.0, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.91
MutPred		0.99		Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);.;Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);.;Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);Loss of disorder (P = 0.0662);.;
MVP		1.0
MPC		0.56
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357093; hg19: chr17-41258503; COSMIC: COSV58800783; COSMIC: COSV58800783;