rs28897743
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong
The NM_000059.4(BRCA2):c.7007G>A(p.Arg2336His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000062 in 1,450,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336L) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 missense, splice_region
NM_000059.4 missense, splice_region
Scores
1
8
7
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 4.66
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-T is described in Lovd as [Pathogenic].
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 13-32346896-G-A is Pathogenic according to our data. Variant chr13-32346896-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38077.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32346896-G-A is described in UniProt as null. Variant chr13-32346896-G-A is described in UniProt as null. Variant chr13-32346896-G-A is described in UniProt as null. Variant chr13-32346896-G-A is described in Lovd as [Likely_pathogenic]. Variant chr13-32346896-G-A is described in Lovd as [Pathogenic]. Variant chr13-32346896-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.7007G>A | p.Arg2336His | missense_variant, splice_region_variant | 13/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7007G>A | p.Arg2336His | missense_variant, splice_region_variant | 13/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000620 AC: 9AN: 1450870Hom.: 0 Cov.: 29 AF XY: 0.00000970 AC XY: 7AN XY: 721902
GnomAD4 exome
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9
AN:
1450870
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Cov.:
29
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AC XY:
7
AN XY:
721902
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
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Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:35
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 25, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | A known pathogenic mutation was detected in the BRCA2 gene. This sequence change replaces arginine with histidine at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer, Fanconi anemia, and acute myeloid leukemia (PMID: 22486713, 25395318, 12065746, 16115142, 26968956, 22430266). This variant is also known as 7235G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38077) with 26 submissions, all of which describe it as pathogenic, 3 stars, reviewed by expert panel. In silico predictions show this variant to pathogenic (PMID: 27124784). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16792514, 22505045, 20215541). Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 22399190, 20960228, 21548014, 17576681, 9536098, 22505045). Therefore, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 06, 2018 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP1. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 30, 2015 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999037 - |
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
| 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 | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
not provided Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2023 | Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing, producing transcripts skipping exons 13 and exons 12-13, which lead to protein truncation or nonsense-mediated decay (Thomassen et al., 2006; Sanz et al., 2010; Biswas et al., 2011; Mesman et al., 2020); Observed in individuals with personal or family history of BRCA2-related cancers (Martin et al., 2001; Coppa et al., 2014; Bu et al., 2016; Lang et al., 2017; Kowalik et al., 2018; Fanale et al., 2020); Observed in the compound heterozygous or homozygous state in individuals with Fanconi anemia (Howlett et al., 2002; Degrolard-Courcet et al., 2014; Ghazwani et al., 2016); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing.; Also known as 7235G>A; This variant is associated with the following publications: (PMID: 16115142, 15645491, 25556971, 27884173, 28477318, 28541631, 11304778, 29310832, 34290354, 32438681, 15026808, 28888541, 33754277, 31558676, 31921681, 29176636, 20215541, 18489799, 22505045, 22486713, 24301060, 21719596, 18451181, 16825431, 16792514, 25395318, 26968956, 27082205, 28294317, 28503720, 28476184, 17924331, 29297111, 28152038, 29907814, 28724667, 25186627, 29084914, 29387975, 30040829, 29565420, 15356654, 12065746, 32854451, 32398771, 33293522, 30214071, 29446198, 30825404, 31065452, 31131967, 34026625, 31825140, 31589614, 32719484, 32853339, 30787465, 35886069, 35494038, 34515413, 34178674, 35382848) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2023 | The BRCA2 c.7007G>A; p.Arg2336His variant (rs28897743) is reported in the literature in individuals affected with breast and/or ovarian cancer and Fanconi anemia (Ahmad 2012, Coppa 2014, Fanale 2020, Ghazwani 2016). This variant is also reported in ClinVar (Variation ID: 38077) 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 occurs in the last nucleotide of exon 13, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with this, transcript analyses demonstrate skipping of exon 13 or exons 12 and 13 in patient cells carrying this variant (Biswas 2011, Houdayer 2012, Sanz 2010). Based on the above information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Ahmad J et al. Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. Clin Genet. 2012 Dec;82(6):594-8. PMID: 22486713. Biswas K et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011 Sep 1;118(9):2430-42. PMID: 21719596. Coppa A et al. Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. Breast Cancer Res Treat. 2014 Dec;148(3):629-35. PMID: 25395318. Fanale D et al. Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2. Cancers (Basel). 2020 Aug 25;12(9):2415. PMID: 32854451. Ghazwani Y et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genet. 2016 Apr;209(4):171-6. PMID: 26968956. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. PMID: 22505045. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. PMID: 20215541. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 16, 2021 | In the published literature, in vitro functional studies have shown that this variant has a deleterious effect on BRCA2 mRNA splicing and causes the synthesis of BRCA2 mRNA without exons 12 and/or 13 (PMIDs: 22505045 (2012), 16792514 (2006)). This variant has also been reported in affected individuals with breast and/or ovarian cancer as well as Fanconi anemia (PMIDs: 30825404 (2019), 25395318 (2014), 18489799 (2008), 12065746 (2002)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 26, 2022 | PP5, PM2, PM3, PS3, PS4_moderate - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg2336His variant has been previously reported in the literature and by our laboratory. It has been reported in the literature in 7 out of 12688 proband chromosomes (Barber 2005, Easton 2007, Machackova 2008, Sanz 2010) in individuals with hereditary breast cancer, male breast cancer and AML. It has also been reported by our laboratory in one individual who met criteria for hereditary breast and ovarian cancer testing. The p.Arg2336His variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. It is listed in dbSNP database (ID#: rs28897743), but no frequency information was provided. This variant was shown to induce aberrant splicing resulting in the deletion of the 70-bp exon 13 from the mRNA and causes a frameshift and premature stop codon in exon 14 (Thomassen 2006). Mutations causing frameshift and truncation of the BRCA2 protein have been shown to be clinically important, and loss of function of the BRCA2 gene represents an established disease mechanism in hereditary breast cancer patients. In addition, functional assays have shown a reduction in the full-length transcript production compared with wild-type cells, hypersensitivity to various DNA damaging agents, defect in HR-mediated DNA repair and an increase in genomic instability has been reported (Biswas 2011, Farrugia 2008). In summary, based on the above information, this variant is classified as Pathogenic. - |
Fanconi anemia complementation group D1 Pathogenic:3
| Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 26, 2002 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2024 | The c.7007G>A pathogenic mutation (also known as p.R2336H), located in coding exon 12 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7007. This changes the amino acid at codon 2336 from arginine to histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple families affected with breast and/or ovarian cancer (Claes K et al Br .J. Cancer. 2004 Mar;90:1244-51; Machackova E et al. BMC Cancer. 2008 May;8:140; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Coppa A et al. Breast Cancer Res. Treat. 2014 Dec;148:629-35; Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620; Fanale D et al. Cancers (Basel) 2020 Aug;12(9)). This mutation has also been reported in both a homozygous and compound heterozygous state in individuals diagnosed with Fanconi Anemia and AML (Barber LM et al. Br. J. Haematol. 2005 Sep;130:796-7; Ghazwani Y et al. Cancer Genet 2016 Apr;209(4):171-6). In addition, the c.7007G>A mutation has been shown to result in a deletion of exon 13 from the mRNA transcript, causing a frameshift and a premature stop codon in exon 14 (Ambry internal data; Farrugia D et al. Cancer Res. 2008 May;68:3523-31; Thomassen M et al. Genet. Test. 2006 Summer;10:116-20; Biswas K et al. Blood. 2011 Sep;118:2430-42; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Houdayer C et a. Hum. Mutat. 2012 Aug;33:1228-38). A multifactorial likelihood ratio analysis that included co-segregation, tumor pathology, co-occurrence and family history data determined this alteration to be pathogenic (Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). Of note, this alteration is also designated as 7235G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This variant alters the conserved, last nucleotide c.G of exon 13 of the BRCA2 gene and is predicted to affect RNA splicing. This variant is also known as p.Arg2336His based on predicted change at the protein level. RNA studies have shown that this variant causes the out-of-frame skipping for exon 13 and exons 12 and 13 in carrier RNA (PMID: 16792514, 18489799, 20215541, 22505045). This variant has also been shown to poorly rescue BRCA2 deficiency and confer hypersensitivity to DNA damaging agents in mouse embryonic stem cells (PMID: 21719596). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 16792514, 20215541, 22505045, 30192042), and the variant is reported to cosegregate with disease with a likelihood ratio of 48.5651 (PMID: 31131967). This variant has also been observed in individuals affected with Fanconi anemia in compound heterozygosity with a pathogenic BRCA2 variant (PMID: 12065746, 24301060) or in homozygosity (PMID: 26968956). 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:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2336 of the BRCA2 protein (p.Arg2336His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, Fanconia anemia, and acute myelogenous leukemia (PMID: 12065746, 16115142, 22430266, 22486713, 25395318, 26968956). This variant is also known as 7235G>A. ClinVar contains an entry for this variant (Variation ID: 38077). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 27124784). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exons 12 and/or 13 and introduces a premature termination codon (PMID: 16792514, 20215541, 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.7007G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 9536098, 17576681, 20960228, 21548014, 22399190, 22505045). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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 | Jul 23, 2020 | Variant summary: BRCA2 c.7007G>A (p.Arg2336His) alters a conserved last nucleotide located within exon 13 comprising the exonic splice region. At the protein level, it results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes splicing through the canonical 5' splicing donor site. Several publications report experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 13 (example, Sanz_2010, Thomassen_2006, Claes_2004). The variant was absent in 247772 control chromosomes. c.7007G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and Fanconi Anemia (example, Sanz_2010, Thomassen_2006, Konstantopoulou_2008, Ahmad_2012, Biswas_2011, Beristain_2010, Brooks_2006, Ghazwani_2016, Gorski_2004, Peixoto_2014, Siraj_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to rescue the lethality of BRCA2-null mouse embryonic stem cells (Biswas_2011). Fourteen 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 (n=14)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Feb 10, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 21, 2024 | The BRCA2 c.7007G>A variant is predicted to result in the amino acid substitution p.Arg2336His. This variant occurs at the last nucleotide of exon 13 and is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). Analysis of patient mRNA showed that this variant leads to exon skipping (Sanz et al. 2010. PubMed ID: 20215541; Houdayer et al. 2012. PubMed ID: 22505045). This variant has been reported to be causative for breast and ovarian cancer (Ahmad et al. 2012. PubMed ID: 22486713; Alhuqail et al. 2018. PubMed ID: 29297111; Table S3, Sun et al. 2017. PubMed ID: 28724667). This variant has also been documented in the compound heterozygous or homozygous state in patients with autosomal recessive Fanconi anemia (Degrolard-Courcet et al. 2014. PubMed ID: 24301060; Ghazwani et al. 2016. PubMed ID: 26968956). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38077/). We classify this variant as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Vest4
MutPred
Loss of glycosylation at T2331 (P = 0.1361);Loss of glycosylation at T2331 (P = 0.1361);
MVP
MPC
0.067
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at