rs62625308
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.3607C>T(p.Arg1203Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,832 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 stop_gained
ENST00000357654.9 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.16
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-43091924-G-A is Pathogenic according to our data. Variant chr17-43091924-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17671.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091924-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091924-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3607C>T | p.Arg1203Ter | stop_gained | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3607C>T | p.Arg1203Ter | stop_gained | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152042Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:48Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:16Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Oct 24, 2023 | This sequence change creates a premature translational stop signal (p.Arg1203*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671) classified as pathogenic . For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 13, 2023 | Criteria applied: PVS1,PM5_STR - |
| not provided, no classification provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 08, 2018 | This c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is predicted to introduce a premature translational termination codon. This variant is extremely rare in the general population according to the gnomAD database. It has been reported in multiple unrelated patients with breast cancer or ovary cancer [2PMID: 7894493, 21324516, 22006311, 22752604, 24218521, 24010542].Therefore, the c.3607C>T (p.Arg1203*) variant in the BRCA1 gene is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 18, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.3607C>T;p.(Arg1203*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17671; PMID: 21324516; PMID: 22006311; PMID: 24010542; PMID: 22752604) - PS4. The variant is present at low allele frequencies population databases (rs62625308 – gnomAD 0.0001195%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 7894493) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| 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 | Baylor Genetics | Nov 23, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Apr 11, 2016 | - - |
| 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, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 07, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 16, 2015 | - - |
not provided Pathogenic:9
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg1203X variant has been previously reported in the literature in 7 of 12470 individuals with hereditary breast or ovarian cancer (Selected publications: Konstantopoulou 2008, Manguoglu 2003, Borg 2010, Kim 2012). The variant was also reported 22 times in the UMD database ase "causal" and 31 times in the BIC database as "clinically important". The variant was also reported 1 time in the ESP project at low frequency (0.0002) and by dbSNP (ID: rs62625308). This variant leads to a premature stop codon at position 1203, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. - |
| 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 | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 12, 2021 | - - |
| 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 | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals with a personal and/or family history of BRCA1-related cancers (Friedman 1994, Walsh 2011, Zhang 2011, Konstantopoulou 2014, Sung 2017); 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 (Lek 2016); Also known as 3726C>T; This variant is associated with the following publications: (PMID: 31372034, 31825140, 32832836, 32710294, 7894493, 31447099, 21324516, 25525159, 31159747, 30720243, 28176296, 29446198, 30555256, 30720863, 30702160, 29310832, 28993434, 29470806, 29752822, 29339979, 28961279, 28324225, 27831900, 26848529, 27157322, 26300996, 27848044, 26709275, 25011685, 25722380, 25637381, 22752604, 22006311, 26010302, 25863477, 24010542, 25371446, 26028024) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 02, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 05, 2019 | This variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in many individuals with breast and/or ovarian cancer in the published literature (PMIDs: 7894493 (1994), 24218521 (2014), 24010542 (2014), 22752604 (2012), 22006311 (2011), 21553119 (2012), 21324516 (2011), 20104584 (2010), 12655560 (2003), 30702160 (2019), 30555256 (2018), and 28993434 (2018)). The frequency of this variant in the general population, 0.000018 (2/113500 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Familial cancer of breast Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change creates a premature translational stop signal at codon 1203, p.(Arg1203*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families affected by breast and ovarian cancer and was shown to segregate with disease in one family (PMID: 21324516, 22006311). This sequence change is also known as 3726C>T in the literature. This mutation has been described in the mutation database ClinVar (Variation ID:17671). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 10, 2024 | Criteria applied: PVS1,PM5_STR - |
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Arg1203X variant in BRCA1 has been reported in >40 individuals with BRCA1-associated cancers (Friedman 1994, Manguoglu 2003, Walsh 2011, Solano 2012, Kim 2012, Juwle 2012, Couch 2015, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/17194 East Asian and 2/111402 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs62625308). This nonsense variant leads to a premature termination codon at position 1203, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282311.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change creates a premature translational stop signal (p.Arg1203*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs62625308, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 7894493, 21324516, 22006311, 22752604, 24010542). It has also been observed to segregate with disease in related individuals. This variant is also known as 3726C>T. ClinVar contains an entry for this variant (Variation ID: 17671). For these reasons, this variant has been classified as Pathogenic. - |
| 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2019 | Variant summary: BRCA1 c.3607C>T (p.Arg1203X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251014 control chromosomes. c.3607C>T has been reported in the literature in numerous individuals affected with hereditary or early-onset breast and/or ovarian cancer (ie. Friedman_1994, Meindl_2002, Kim_2012, Juwle_2012, Solano_2013, Stavropoulo_2013). 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. 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014). All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 13, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Dec 20, 2013 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | The p.R1203* pathogenic mutation (also known as c.3607C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3607. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported in multiple families with breast and/or ovarian cancer across various ethnicities (Friedman LS et al. Nat. Genet. 1994 Dec;8:399-404; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Hirasawa A et al. Jpn. J. Clin. Oncol. 2014 Jan;44:49-56; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this alteration is also designated as 3726C>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 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. - |
Inherited breast cancer and ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Sep 06, 2024 | PVS1,PM5_Strong - |
Breast neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Feb 16, 2017 | - - |
BRCA1-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 22006311, 22752604, 22798144, 23961350, 23536787, 24010542, 24218521, 25452441, 28324225, 28993434, 29310832, 29339979, 29470806, 29752822, 30555256, 30720863, 31372034, 33151324, 33471991; Leiden Open Variation Database DB-ID BRCA1_001405) and an individual affected with clear cell renal cell carcinoma (PMID: 33442023). This variant has been identified in 3/251014 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. - |
Ovarian carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 11, 2021 | - - |
BRCA1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2023 | The BRCA1 c.3607C>T variant is predicted to result in premature protein termination (p.Arg1203*). This variant has been widely reported in individuals with hereditary breast and ovarian cancer (see for example, Table 2a, Friedman et al. 1994. PubMed ID: 7894493; Table 1, Meindl et al. 2002. PubMed ID: 11802209). This variant was also reported as germline variant in a patient with renal cell carcinoma (Table S3, Santos et al. 2021. PubMed ID: 33442023). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243941-G-A), and it is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17671/). Taken together, this variant is interpreted as pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
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Pathogenic
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Uncertain
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Benign
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Benign
N
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Benign
A;A;A;A;A;A;D;D;D;D;D;D;D;D
Vest4
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RBP_binding_hub_radar
RBP_regulation_power_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at