rs41293465

chr17-43045767-G-Achr17-43045767-G-Cchr17-43045767-G-T

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:40 O:1
• Conservation: PhyloP100: 0.950

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 76 pathogenic variants in the truncated region.
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PP5: Variant 17-43045767-G-A is Pathogenic according to our data. Variant chr17-43045767-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55601. Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045767-G-A is described in Lovd as [Pathogenic]. Variant chr17-43045767-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5503C>T	p.Arg1835Ter	stop_gained	23/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5503C>T	p.Arg1835Ter	stop_gained	23/23	1	NM_007294.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251278 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461874 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:40Other:1

Revision: reviewed by expert panel

LINK:

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12Other:1

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 14, 2014	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 20, 2015	The heterozygous variant in the BRCA1 gene (c.5503C>T; p.Arg1835*)is considered pathogenic. This change results in a premature stop codon interrupting an important functional domain BRCT2 (PMID: 11739404) and premature truncation results in impaired function. This variant has been previously published in 2 individuals of Punjabi ethnicity and part of a cohort of unrelated Pakistani individuals with breast and ovarian cancer (PMID: 16998791), though the paper has no additional information on the phenotype of the affected individuals. This variant has also been seen in multiple affected individuals by other clinical labs (SCV000109430, SCV000145551, SCV000186917, SCV000210227, SCV000077033). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Sep 13, 2023	This sequence change creates a premature translational stop signal (p.Arg1856*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs41293465, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and bladder cancer (PMID: 8554067, 10486320, 11802209, 16683254, 19949876, 23704984, 27553291). This variant is also known as 5622C>T. ClinVar contains an entry for this variant (Variation ID: 55601). Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no assertion provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 22, 2023	Criteria applied: PS3,PS4,PM4,PM2_SUP -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2020	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PerkinElmer Genomics	Jul 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Karolinska University Hospital, Karolinska University Hospital	Apr 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 03, 2022	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.5503C>T, which results in the creation of a premature stop codon at amino acid position 1835, p.Arg1835*. This sequence change is reported in the gnomAD database with a global population frequency of 0.0012% (dbSNP rs41293465). This sequence change has been described in multiple individuals and families with breast, ovarian and bladder cancer (PMID: 27553291, 8554067, 10486320,11802209, 16683254,19949876, 23704984,31528241). Of note, this alteration is also designated as 5622C>T in published literature. Functional studies have shown that although this variant does not trigger nonsense-mediated mRNA decay (PMID: 12393792), it results in a truncated protein lacking the last few amino acid residues and displayed loss of activity (PMID: 11157798). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	Criteria applied: PVS1, PM2, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2023	Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Reported in association with hereditary breast and/or ovarian cancer (Serova et al., 1996; Meindl, 2002; Rashid et al., 2006; van der Hout et al., 2006; Borg et al., 2010; Cunningham et al., 2014; Kwong et al., 2016); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5622C>T; This variant is associated with the following publications: (PMID: 12360400, 24504028, 16998791, 29176636, 8554067, 25682074, 26541979, 25085752, 26898890, 26848529, 21559243, 17591843, 11260866, 9796975, 27767231, 25066507, 16683254, 27553291, 15026808, 29922827, 28888541, 34282142, 20727672, 26404129, 10505028, 18465347, 10486320, 26028024, 25722380, 27157322, 12601471, 12960223, 18375895, 11920621, 16782705, 12393792, 24578176, 9760198, 20104584, 24728189, 27194814, 23569316, 16644204, 11739404, 11802209, 9667259, 10699917, 16528604, 26976419, 24249303, 19949876, 23704984, 28324225, 29339979, 29752822, 29470806, 28724667, 28993434, 29310832, 30702160, 29446198, 31090900, 31528241, 30855176, 30291343, 32338768, 33758026, 35356428, 33804961, 35377489, 33087929, 30875412, 32710294, 32719484, 31825140, 33654310, 36988593, 30209399) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	Nov 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change creates a premature translational stop signal (p.Arg1835*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs41293465, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and bladder cancer (PMID: 8554067, 10486320, 11802209, 16683254, 19949876, 23704984, 27553291). This variant is also known as 5622C>T. ClinVar contains an entry for this variant (Variation ID: 55601). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 11739404). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 12400015, 21922593; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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	Dec 28, 2020	Variant summary: BRCA1 c.5503C>T (p.Arg1835X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251278 control chromosomes. c.5503C>T has been widely reported in the literature in multiple individuals 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cancer Genomics Lab, PINUM Cancer Hospital	Feb 20, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 29, 2021	This variant changes 1 nucleotide in exon 23 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study reported that this variant failed to complement human haploid cells (30209399). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 8554067, 9760198, 10505028, 11260866, 16644204, 16683254, 20104584, 20727672, 24504028, 24549055, 25682074, 26187060, 27153395, 28324225, 28423363, 29339979, 29470806, 31209999). This variant has been identified in 3/251278 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2022	The p.R1835* pathogenic mutation (also known as c.5503C>T), located in coding exon 22 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5503. This changes the amino acid from an arginine to a stop codon within coding exon 22. This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Rashid MU et al. BMC Cancer. 2016 08;16:673; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48:58-63; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Apessos A et al. Cancer Genet. 2018 01;220:1-12). 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). Of note, this alteration is also designated as 5622C>T in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2020	- -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 14, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 21, 2015	- -

Stomach cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jan 01, 2020

This variant is a single amino acid change from Arginine to a termination codon at amino acid residue 1835 of the BRCA1 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in BRCA1 are known to be pathogenic. -

Lung cancer;C0346153:Familial cancer of breast;C0919267:Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 08, 2021

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Arg1835X variant is reported in the literature in 12/7062 proband chromosomes of individuals with breast and ovarian cancer (Bellacosa 2010, Borg 2010, Dizin 2006, Evans 2003, Ferla 2007, Frank 1998, Magnard 2002, Ramus 2007, Rashid 2006, Spurdle 2008); it was not found in any of the 484 control chromosomes. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs#:41293465) but no frequency information was provided, and is therefore, not very informative for assessing the population frequency. The alteration leads to a premature stop codon at position 1835 which is predicted to lead to a truncated or absent protein and loss of function, which is an established disease mechanism for the BRCA1 gene in hereditary breast and ovarian cancer. The variant is reported in the BIC database (x66) and UMD database (x20) as a variant of clinical significance. In addition, two functional studies using the yeast two-hybrid screen and glutathione-S-transferase (GST) pull-down assay, determined that the variant abolished interaction of BRCA1 with two proteins: Acetyl Coenzyme A (CoA) Carboxylase and PABP (Dizin 2006, Magnard 2002). In summary, based on the above information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

D

BayesDel_noAF

Pathogenic

0.55

Cadd

Pathogenic

37

Dann

Uncertain

0.99

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.59

D

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Vest4

0.73

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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: rs41293465; hg19: chr17-41197784; COSMIC: COSV58789996;