17-43106478-A-G

Variant names:

• chr17-43106478-A-G
• rs80357064
• NM_007294.4:c.190T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001407853.1(BRCA1):​c.2T>C​(p.Met1?) variant causes a start lost, splice region change. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 NM_001407853.1 start_lost, splice_region
• 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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.190T>C	p.Cys64Arg	missense_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.190T>C	p.Cys64Arg	missense_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3

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

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.190T>C (p.Cys64Arg) variant has been reported in the published as a founder variant in hereditary breast and ovarian cancer (HBOC) families in the Italian population (PMIDs: 19287957 (2009), 24516540 (2014)). This variant has also been observed in individuals of varying ethnicities with personal or family histories of breast and/or ovarian cancer (PMIDs: 28111427 (2017), 29446198 (2018), 29752822 (2018), 30726305 (2019), 30972954 (2019), 34072659 (2021), 35980532 (2022), 38386807 (2024)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMIDs: 24516540 (2014), 25823446 (2015), 26246475 (2015)). The variant is located in a region that is considered important for protein function and/or structure (PMID: 11573085 (2001)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Jan 01, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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). ClinVar contains an entry for this variant (Variation ID: 54394). 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: 19287957, 24516540, 25823446). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 24516540; Invitae). 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. For these reasons, this variant has been classified as Pathogenic. -

Jan 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial cancer of breast Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 31, 2014

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

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;.;.;.;.;.;.;.;.
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;