rs80357201
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.3296C>T(p.Pro1099Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 2.53
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 Benign. Variant got -10 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.14682075).
BP6
Variant 17-43092235-G-A is Benign according to our data. Variant chr17-43092235-G-A is described in ClinVar as [Benign]. Clinvar id is 41816.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092235-G-A is described in Lovd as [Benign]. Variant chr17-43092235-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3296C>T | p.Pro1099Leu | missense_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3296C>T | p.Pro1099Leu | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.000178 AC: 27AN: 152038Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000303 AC: 76AN: 250562Hom.: 0 AF XY: 0.000340 AC XY: 46AN XY: 135434
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GnomAD4 exome AF: 0.000272 AC: 398AN: 1461326Hom.: 0 Cov.: 39 AF XY: 0.000292 AC XY: 212AN XY: 726948
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GnomAD4 genome 0.000177 AC: 27AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74388
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:26
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:10
| Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000000000309 - |
| Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Counsyl | Feb 25, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
| Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 23, 2021 | The BRCA1 c.3296C>T variant is classified as Benign (BS1, BP6) - |
not specified Uncertain:1Benign:4
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers descrive as non-pathogenic; ClinVar: 4 B/LB - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:4
| Likely benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Pro1099Leu variant was identified in 22 of 114568 proband chromosomes (frequency: 0.0002) from individuals or families with breast or ovarian cancer (Judkins 2005, Simard 2007, Borg 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357201) as "With other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx and 7 other submitters; as likely benign by three submitters; as uncertain significance by one submitter), MutDB, LOVD 3.0 (10x), UMD-LSDB (19x as neutral), BIC Database (23x with no clinical importance), and in ARUP Laboratories (not pathogenic or of no clinical significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4277delC, p.Thr1426Asns*22 and c.5353delA, p.Thr1785Leufs*6), increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance. The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 87 of 276300 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6452 chromosomes (freq: 0.0005), Latino in 17 of 34400 chromosomes (freq: 0.0005), European in 30 of 126188 chromosomes (freq: 0.0002), East Asian in 1 of 18866 chromosomes (freq: 0.00005), Finnish in 14 of 25458 chromosomes (freq: 0.0006), and South Asian in 22 of 30778 chromosomes (freq: 0.0007); it was not observed in the African or Ashkenazi Jewish populations. The p.Pro1099 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A few cancer research articles identified this variant in trans with known deleterious mutations (917delTT and E1060X) in clinical specimens, increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance (Judkins 2005, Judkins 2005, Spurdle 2008). In addition, the variant was classified as neutral with probability of being deleterious is 3.09√ó10-11 by a computational model for BRCA1 and BRCA2 variants that factored in data on segregation, co-occurrence, personal and family histories, and pathology (Lindor 2012). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 21, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 25, 2016 | Variant summary: The variant c.3296C>T affects a conserved nucleotide, leading to amino acid change from Pro to Leu. 3/4 in-silico tools predict this variant to be damaging, however they are not definite. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0.00026 (32/122380 chromosomes), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). However, the frequency data should still suggest that this variant is likely to be a rare polymorphism. In reputable databases (BIC and UMD), the variant has been reported to co-occur with multiple deleterious pathogenic variants in BRCA1 (p.Glu1060Ter, c.2376_2376delG and c.798_799delTT) as well as in BRCA2 (c.4277delC and c.5353delA). In addition, the variant is also known to be present with a deleterious BRCA1 variant p.Glu1060Ter (Judkins_2005), a definite evidence for benign outcome. Multifactorial probability model studies also show the variant to have a very low probability of being deleterious. Multiple clinical laboratories, reputable databases, and literature classify this variant as benign/polymorphism. Taken all together, this variant has been classified as Benign. - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 31, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 19, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Jan 21, 2016 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 13, 2020 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1
| Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 21, 2021 | - - |
BRCA1-related disorder Benign:1
| Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 27, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;P
Vest4
MVP
MPC
0.27
ClinPred
T
GERP RS
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gMVP
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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