rs80357446
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001407841.1(BRCA1):c.-8+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BRCA1
NM_001407841.1 splice_donor, intron
NM_001407841.1 splice_donor, intron
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 3.48
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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 4, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115729-C-A is Pathogenic according to our data. Variant chr17-43115729-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 54200.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic]. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461168Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726864
GnomAD4 exome
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AC:
3
AN:
1461168
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Cov.:
30
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2
AN XY:
726864
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8Uncertain:1Other:1
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This missense variant replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 16912212, 18159056, 22711857, 22713736, 28486781) and multiple suspected hereditary breast and ovarian cancer families (PMID: 12048272, 16267036, 19241424). This variant is also reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 156.1745 and 41.2405, respectively (PMID: 31131967). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 07, 2012 | - - |
| 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 | Counsyl | Feb 01, 2017 | - - |
| not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 05, 2023 | A known pathogenic variant was detected in the BRCA1 gene in this specimen. This sequence change replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein (p.Cys44Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not found in gnomAD exomes. This variant has been reported in individuals affected with breast and or ovarian cancer (PMID: 23633455, 18159056, 25777348, 16267036). This variant is also known as 250G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54200) and classifies this variant as Pathogenic, rated 3 stars, reviewed by expert panel. Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID: 20103620, 16403807, 23161852, 21725363, 27272900). Therefore, this variant has been classified as pathogenic. - |
| 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 = 0.999964 - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 18, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single amino acid change from Cysteine to Phenylalanine at amino acid residue 44 of the BRCA1 protein. The Cysteine residue is highly conserved among species and is located in a functional domain of the protein and a region known to interact with multiple proteins. There is a large physiochemical difference between Cysteine acid and Phenylalanine (Grantham Score 205). To our knowledge, this variant is not present in population databases (rs80357446). This variant is also known as c.250G>T in the literature and it was shown to disrupt normal protein function by a yeast two-hybrid E3 Ub-ligase activity assay, a homology directed recombination assay, a BARD1 binding assay and a centrosome amplification assay (PMID: 20103620, 21725363). In addition, several individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome were found to carry this variant (PMID: 22713736). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. The mutation database Clinvar contains entries for this variant (Variation ID: 54200). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2022 | Published functional studies demonstrate a damaging effect: disrupted homology-directed repair and BARD1 binding, and loss of E3 ubiquitin ligase activity and centrosome amplification (Morris 2006, Ransburgh 2010, Kais 2012, Starita 2015, Findlay 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (John 2007, Hall 2009, Jalkh 2012, Lolas Hamameh 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Also known as 250G>T; This variant is associated with the following publications: (PMID: 24312913, 26187060, 23161852, 16403807, 25823446, 28486781, 30350268, 15235020, 20103620, 11320250, 22713736, 12732733, 21725363, 23633455, 25085752, 25777348, 25814778, 18159056, 19241424, 27272900, 28202063, 28364669, 29446198, 30209399, 33087888, 31131967, 24389207, 20104584, 8944023) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 17, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2018 | Variant summary: BRCA1 c.131G>T (p.Cys44Phe) results in a non-conservative amino acid change located in the RING binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245760 control chromosomes (gnomAD). The variant, c.131G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Alsop_2012, Jalkh_2012, El Saghir_2015, Christie_2017, etc). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies found that the variant significantly impacts proper BRCA1 protein function (Kais_2012, Morris_2006,Ransburgh_2010, Towler_2013, and Thouvenot_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 04, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 44 of the BRCA1 protein (p.Cys44Phe). 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 (PMID: 16267036, 18159056, 23633455, 25777348). This variant is also known as 250G>T. ClinVar contains an entry for this variant (Variation ID: 54200). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 20103620, 21725363, 22843421, 23161852, 27272900). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21922593, 25823446, 27083775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Dec 17, 2015 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Nov 10, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 17, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2021 | The p.C44F pathogenic mutation (also known as c.131G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 131. The cysteine at codon 44 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). Based on internal structural assessment, this alteration is predicted to disrupt formation of zinc binding site 1 and overall folding of the BRCA1 protein. This is consistent with Brzovic PS et al (2010), who showed that experimentally altering ligands at this residue yields BRCA1 RING domains that fail to fold properly (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8:833-7). Multiple functional studies have shown that this alteration is deleterious including a centrosome amplification assay, a homology directed repair assay, a single stranded annealing assay and a high throughput cell survival assay (Kais Z et al. Oncogene. 2012 Feb;31:799-804; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature, 2018 Sep;). This mutation has been identified in multiple breast and/or ovarian cancer families in the literature (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun;10:7; George J et al. Clin. Cancer. Res. 2013 Jul;19:3474-84; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, two other alterations at the same codon, p.C44Y and p.C44S, have been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This missense variant replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 16912212, 18159056, 22711857, 22713736, 28486781) and multiple suspected hereditary breast and ovarian cancer families (PMID: 12048272, 16267036, 19241424). This variant is also reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 156.1745 and 41.2405, respectively (PMID: 31131967). 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. - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;N;D;D;D;N;.;N;N;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen
0.99, 0.97, 1.0
.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);
MVP
MPC
0.15
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at