17-43106478-A-G

Position:

• chr17-43106478-A-G

Variant summary

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

The ENST00000357654.9(BRCA1):​c.190T>C​(p.Cys64Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C64Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:2 O:1
• Conservation: PhyloP100: 4.88

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 17 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43106477-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54400.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-43106478-A-G is Pathogenic according to our data. Variant chr17-43106478-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 54394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106478-A-G is described in Lovd as [Pathogenic]. Variant chr17-43106478-A-G is described in Lovd as [Pathogenic]. Variant chr17-43106478-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.190T>C	p.Cys64Arg	missense_variant	4/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.190T>C	p.Cys64Arg	missense_variant	4/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450124 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722022

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 16, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 29, 2019	This variant has been reported as a founder mutation in hereditary breast/ovarian cancer (HBOC) families in the Italian population (PMID: 24516540 (2014), 19287957 (2009)) and has also been observed in multiple other individuals/families of various ethnicities with HBOC (PMID: 29752822 (2018), 29446198 (2018), 28111427 (2017)). Functional studies indicated that this variant has a damaging effect on the function of the protein (PMID: 24516540 (2014), 26246475 (2015), 25823446 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This missense variant replaces cysteine with arginine at codon 64 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant alters a conserved cysteine in the RING domain and functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, BARD1 binding, ubiquitin E3 ligase, a haploid cell proliferation, sensitivity to ionizing radiation and PARP inhibitors and chromosomal instability assays (PMID: 24516540, 25823446, 26246475, 28398198, 30209399). This variant has been reported in over 90 individuals affected with breast and ovarian cancer and in suspected hereditary breast and ovarian cancer families in Europe, Asia and South America (PMID: 8875986, 11462239, 14531499, 16140926, 19287957, 24516540, 24249303, 27741520, 28993434, 30103829, 30702160, 30972954, 34906479). Haplotype analysis indicates that this variant is a founder mutation in Italy (PMID: 24516540). This variant has been reported to confer lower risk for breast cancer and high risk for ovarian cancer compared to other pathogenic BRCA1 variants (PMID: 34906479). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2022	The p.C64R pathogenic mutation (also known as c.190T>C), located in coding exon 3 of the BRCA1 gene, results from a T to C substitution at nucleotide position 190. The cysteine at codon 64 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation is located in the highly conserved RING-finger motif of BRCA1, has been observed to segregate with disease in multiple breast and ovarian cancer families, and has been described as an Italian founder mutation (Jakubowska A et al. Hum. Mutat. 2001;18:149–156; Willems P et al. Int J Oncol. 2009;34(4):1005-15; Marchina E et al. Oncol Rep. 2010;24(6):1661-7; Caleca L et al. PLoS ONE, 2014 Feb;9:e86924). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, other functional studies have shown that p.C64R adversely affects the BRCA1/BARD1 complex formation, and leads to increased sensitivity to ionizing radiation and chromosomal instability (Caleca L et al. PLoS ONE, 2014 Feb;9:e86924; Cochran RL et al. Oncotarget, 2015 Sep;6:25240-51). Of note, this alteration is also referred to as 309T>C in published literature. 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042907, 12732733, 16140926, 20103620, 23161852, 23867111, 26689913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 24516540; Invitae). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 19287957, 24516540, 25823446). ClinVar contains an entry for this variant (Variation ID: 54394). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 8875986, 11462239, 14531499, 21042765, 24249303, 24516540, 27741520). It is commonly reported in individuals of Italian ancestry (PMID: 8875986, 11462239, 14531499, 21042765, 24249303, 24516540, 27741520). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 64 of the BRCA1 protein (p.Cys64Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2020	The p.Cys64Arg variant in BRCA1 has been identified in >50 pan-ethnic individuals with BRCA1-associated cancers and segregated with disease in at least 15 individuals from several families (Caligo 1996, Willems 2009, Marchina 2010, Caleca 2014, Shi 2017, Park 2017, Rebbeck 2018, Cardoso 2018, Palmero 2018, Wen 2018, Li 2019, Deng 2019, Bhaskaran 2019, Breast Cancer Information Core (BIC; https://research.nhgri.nih.gov/bic/). This variant has been described as a founder variant in the Italian population (Caleca 2014). In addition, it has also been reported by other clinical laboratories in ClinVar (Variation ID 54394) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, and in vitro functional studies support an impact on protein function (Willems 2009, Caleca 2014, Cochran 2015, Findlay 2018). Another variant involving this codon (p.Cys64Gly) has been identified in individuals with hereditary breast and ovarian cancer (HBOC) and is currently classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2, PM5, PS3_Supporting, PP1_Strong, PP3. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Benign	0.85
DEOGEN2	Uncertain	0.48	.;T;.;.;.;.;D;.;.;T;T;D;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	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	0.96	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;.;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N;N;D;N;N;D;N;N;.;N;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);.;Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);.;Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);Gain of disorder (P = 0.0218);.;
MVP		1.0
MPC		0.50
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357064; hg19: chr17-41258495;