rs41286290
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4BP6_Very_Strong
The NM_007294.4(BRCA1):c.1001C>T(p.Pro334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,776 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 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 0.973
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 -7 ACMG points.
PM1
In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4
BP4
Computational evidence support a benign effect (MetaRNN=0.26464015).
BP6
Variant 17-43094530-G-A is Benign according to our data. Variant chr17-43094530-G-A is described in ClinVar as [Benign]. Clinvar id is 54099.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094530-G-A is described in Lovd as [Benign].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152006Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251380Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135856
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461770Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59AN XY: 727178
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74236
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ClinVar
Significance: Benign
Submissions summary: Benign:11
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3
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 = 0.000000271 - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2017 | Variant summary: The BRCA1 c.1001C>T (p.Pro334Leu) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. Functional studies show the variant to not affect splicing (Anczukow_2008, Caux-Moncoutier_2009). This variant was found in 2/121404 control chromosomes from ExAC at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005); however, it could still be a rare polymorphism. The variant has been reported in multiple affected individuals via publications and databases, including co-occurrence with other BRCA1 pathogenic variants in other allele (in trans), 2120insA (Judkins_2005), c.66_67delAG (BIC), and an unspecified deleterious variant (Spearman_2008), strongly supporting for benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2021 | This variant is associated with the following publications: (PMID: 17924331, 19471317, 21990134, 18824701, 22753008, 18273839, 16267036, 23893897, 25348012, 18703817, 22045683) - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2019 | 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 | Oct 22, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 13, 2016 | - - |
BRCA1-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 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
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;T;T;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;.;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;.;D;D;D;D
Sift4G
Benign
T;T;T;T;.;D;.;T;D
Polyphen
P;.;.;B;.;.;.;.;.
Vest4
MVP
MPC
0.11
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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