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rs41293455

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_007294.4(BRCA1):c.4327C>T(p.Arg1443Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,954 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic reviewed by expert panel P:45O:1

Conservation

PhyloP100: 1.53
Variant links:
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 17-43082434-G-A is Pathogenic according to our data. Variant chr17-43082434-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17675.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43082434-G-A is described in Lovd as [Pathogenic]. Variant chr17-43082434-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4327C>T p.Arg1443Ter stop_gained 12/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4327C>T p.Arg1443Ter stop_gained 12/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251364
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461838
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
12
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000374
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:45Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:16
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenologica MedicaJan 01, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 1994- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 08, 2014- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterliterature onlyCounsylOct 02, 2014- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 12, 2018This rare nonsense variant c.4327C>T (p.Arg1443*) in the BRCA1 gene is extremely rare in public databases and is predicted to introduce a premature translation termination codon. This variant is considered to be a founder mutation (PMID 15883839 ) and has been observed in multiple unrelated individuals with breast cancer (PMID 10422801,21324516, 7894491). Therefore, this c.4327C>T (p.Arg1443*) variant in the BRCA1 gene is classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingBRCAlab, Lund UniversityAug 26, 2022- -
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Nov 14, 2013- -
Pathogenic, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Apr 22, 2016Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Pathogenic, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganApr 21, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 29, 2016- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 24, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 23, 2020- -
not provided Pathogenic:11
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 25, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 02, 2023PP5, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 03, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenJun 17, 2021- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 06, 2023The BRCA1 c.4327C>T (p.Arg1443*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 32885271 (2021), 32854451 (2020), 32341426 (2020), 32029870 (2020), 28724667 (2017)) and endometrial cancer (PMID: 28049106 (2017)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010). The frequency of this variant in the general population, 0.000085 (3/35428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 04, 2019Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4446C>T; This variant is associated with the following publications: (PMID: 23233716, 26028024, 25371446, 27463008, 28127413, 19656415, 9625424, 7493024, 8533757, 28111427, 29446198, 16905680, 25525159, 18680205, 23341105, 22401979, 15382066, 20694749, 15883839, 10090482, 23199084, 17148771, 11307153, 10486320, 7894491, 21324516, 27469594, 27184744, 27393621, 26541979, 28049106, 27783335, 16030099, 25236687, 27533253, 26976419, 21120943, 27221827, 26911350, 25504618, 17688236, 27286788, 25085752, 27553291, 28283652, 28392550, 19863560, 15726418, 25652403, 17591843, 19241424, 11179017, 17221156, 22798144, 9792861, 10682662, 26295337, 19329713, 16417652, 10422801, 15951958, 18821011, 10984458, 8990217, 21203900, 8571953, 28985766, 26681312, 28993434, 29907814, 29470806, 28724667, 30702160, 30630528, 30078507, 30720243, 30322717, 30093976, 31090900, 32467295, 33646313, 11597388, 31447099, 31825140, 32341426, 32885271, 30875412, 31742824, 33087929) -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergOct 17, 2023This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Not enough evidence -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalAug 19, 2015- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Hereditary breast ovarian cancer syndrome Pathogenic:6Other:1
Pathogenic, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateNov 16, 2021- -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 24, 2019The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers (Vézina 2005, Hall 2009). It has also been identified in 3/35428 Latino chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. In addition, functional studies provide some evidence that this variant results in a truncated protein (Caligo 2009). 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 SCV000282327.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS3_Supporting, PS4. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change creates a premature translational stop signal (p.Arg1443*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16030099, 19656415, 22798144, 23233716). It is commonly reported in individuals of French Canadian ancestry (PMID: 10422801, 11250694, 15883839, 20694749). This variant is also known as 4446C>T. ClinVar contains an entry for this variant (Variation ID: 17675). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Pathology and Molecular Medicine, Queen's UniversityApr 20, 2017- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 15, 2016Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Pathogenic and reported on 04-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 09, 2023This variant changes 1 nucleotide in exon 12 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 reported in at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 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 submittercurationSema4, Sema4Nov 09, 2021- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 24, 2021The p.R1443* pathogenic mutation (also known as c.4327C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4327. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation is a well-known French Canadian founder mutation and has been reported in numerous breast and/or ovarian cancer families to date (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Ghadirian P et al. Clin. Genet. 2009 Nov;76(5):421-6; Janavicius R et al. EPMA J. 2010 Sep;1(3):397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). In addition to French Canadians, this mutation has also been identified in multiple other populations (McKean-Cowdin R et al. Hum. Genet. 2005 May;116(6):497-506; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159(1):131-8; Jalkh N et al. BMC Med Genomics 2017 Feb;10(1):8; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). Of note, this alteration is also designated as 4446C>T and R1443X in some 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. -
not specified Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJul 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 21, 2019The BRCA1 c.4327C>T; p.Arg1443Ter variant (rs41293455), also known as 4446C>T for traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Castilla 1994, de Jonge 2017, Rashid 2016, Sun 2017, Susswein 2016, Zhang 2011). This variant is also described as a founder variant in the French Canadian population (Cavallone 2010, Neuhausen 2000, Tonin 1999, Vezina 2005). It is reported by multiple laboratories in ClinVar (Variation ID: 17675), and found in the general population with a low overall allele frequency of 0.002% (6/246148 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. de Jonge MM et al. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. Eur J Cancer. 2017 Feb;72:215-225. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. Rashid MU et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Tonin PN et al. Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999 May;55(5):318-24. Vezina H et al. Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005 Jul;117(2-3):119-32. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. -
Breast and/or ovarian cancer Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 23, 2023- -
Pathogenic, no assertion criteria providedclinical testingFoulkes Cancer Genetics LDI, Lady Davis Institute for Medical ResearchDec 07, 2015- -
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:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 19, 2021- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -
Pathogenic, no assertion criteria providedcase-controlBioinformatics dept., Datar Cancer Genetics Limited, India-- -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Arg1443X variant has been previously and extensively reported in the literature. In two selected publications, this variant was identified in 18 of 294 individuals with hereditary breast and ovarian cancer (Selected publications: Tonin 1998, Castilla 1994). This variant was identified as a founder French-Canadian mutation and a common haplotype was described; multiple individuals from these families had breast or ovarian cancers; additional data suggest this variant may also have arisen independently at least three times. The variant is described 83 times in the UMD database as "causal" and 126 times in the BIC database as clinically important. The p.Arg1443X variant leads to a premature stop codon at position 1443, 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 hereditary breast and ovarian cancer. 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
0.22
D
BayesDel_noAF
Pathogenic
0.28
Cadd
Pathogenic
35
Dann
Uncertain
0.99
Eigen
Benign
-0.045
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.25
N
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;N;N;N
Vest4
0.87
GERP RS
2.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41293455; hg19: chr17-41234451; COSMIC: COSV58787462; COSMIC: COSV58787462; API