rs41293455
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.4327C>T(p.Arg1443*) 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
Consequence
NM_007294.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | MANE Select | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 23 | NP_009225.1 | ||
| BRCA1 | NM_001407581.1 | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 24 | NP_001394510.1 | |||
| BRCA1 | NM_001407582.1 | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 24 | NP_001394511.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | TSL:1 MANE Select | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 23 | ENSP00000350283.3 | ||
| BRCA1 | ENST00000471181.7 | TSL:1 | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 24 | ENSP00000418960.2 | ||
| BRCA1 | ENST00000470026.6 | TSL:1 | c.4327C>T | p.Arg1443* | stop_gained | Exon 12 of 23 | ENSP00000419274.2 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251364 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461838Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 727220 show subpopulations
Age Distribution
GnomAD4 genome 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74304 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:18
Criteria applied: PVS1,PM5_STR
This 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.
Variant allele predicted to encode a truncated non-functional protein.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The stop gained c.4327C>T (p.Arg1443Ter) variant in the BRCA1 gene as been observed in individual(s) with hereditary breast and ovarian cancer (Kim, Haeyoung et al., 2012). It is commonly reported in individuals of French Canadian ancestry (Cavallone, Luca et al., 2010). This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic (reviewed by expert panel). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.4327C>T in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PVS1; PM5_PTC_Strong
not provided Pathogenic:13
This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Not enough evidence
PP5, PM2_moderate, PS4_moderate, PVS1
The 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). The p.Arg1443Ter variant is reported in ClinVar (Variation ID: 17675) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is found in the general population with an overall allele frequency of 0.0025% (7/282,760 alleles) in the Genome Aggregation Database. The p.Arg1443Ter 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: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ 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. PMID: 7894491. 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. PMID: 20694749. 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. PMID: 28049106. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. PMID: 11250694. 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. PMID: 27553291. 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. PMID: 28724667. 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. PMID: 26681312. 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. PMID: 10422801. 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. PMID: 15883839. 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. PMID: 21324516.
The 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.
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; 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)
Hereditary breast ovarian cancer syndrome Pathogenic:6Other:1
This 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.
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.
The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers and is considered to be a French-Canadian founder mutation (Vézina 2005 PMID:15883839, Hall 2009 PMID:19241424). It has also been identified in 0.002% (1/41432) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. This is corroborated by a functional study that provides some evidence that this variant results in a truncated protein that lacks the BRCT domains (Caligo 2009 PMID:18680205). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 17675). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1_Strong.
Variant 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.
Hereditary cancer-predisposing syndrome Pathogenic:3
The 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.
This 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.
Breast and/or ovarian cancer Pathogenic:2
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
Familial cancer of breast Pathogenic:2
not specified Pathogenic:1
Inherited breast cancer and ovarian cancer Pathogenic:1
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S Pathogenic:1
BRCA1-related cancer predisposition Pathogenic:1
This 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.
Malignant tumor of breast Pathogenic:1
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.
BRCA1-related disorder Pathogenic:1
This variant is also referred to as c.4446C>T in the literature. This nonsense variant found in exon 12 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). This variant has been previously reported as a heterozygous change in individuals with breast and ovarian cancer (PMID: 16030099, 19656415, 22798144, 23233716). The c.4327C>T (p.Arg1443Ter) variant is a founder variant in the French-Canadian population (PMID: 15883839). This variant is present in the latest version of the gnomAD population database at an allele frequency of 0.001% (20/1613954) and thus is presumed to be rare. Based on the available evidence, c.4327C>T (p.Arg1443Ter) is classified as Pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at