rs41286294
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong
The NM_007294.4(BRCA1):c.1534C>T(p.Leu512Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,824 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 Benign (★★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 3.46
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801
BP6
Variant 17-43093997-G-A is Benign according to our data. Variant chr17-43093997-G-A is described in ClinVar as [Benign]. Clinvar id is 37420.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250832Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135590
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GnomAD4 exome AF: 0.000123 AC: 180AN: 1461684Hom.: 0 Cov.: 34 AF XY: 0.0000990 AC XY: 72AN XY: 727118
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GnomAD4 genome 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74316
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ClinVar
Significance: Benign
Submissions summary: Uncertain:4Benign:14
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 23, 2003 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 14, 2016 | - - |
| Benign, 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 1 based on posterior probability = 0.000143 - |
| Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 05, 2012 | - - |
not specified Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 04, 2020 | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2017 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2022 | Variant summary: BRCA1 c.1534C>T (p.Leu512Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251232 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1534C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples- Meindl_2002, Judkins_2005, Jimenez_2009, Plascocinska_2016). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported [BRCA1 c.81_4986del , p.Cys27X; BRCA2 c.8023A>G , p.Ile2675Val; and BRCA2 c.5909C>A, p.Ser1970X (BIC database); BRCA1 c.1570delG, p.Ala524Glnfs (Jimenez_2009); BRCA2 c.1813dupA, p.Ile605AsnfsX11 (internal sample)], providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) reported the variant with conflicting assessments, citing the variant as uncertain significance (n=2), likely benign (n=7), and benign (n=1, expert panel). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BRCA1: BP1, BP2, BS3:Supporting, BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 07, 2015 | - - |
Hereditary cancer-predisposing syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2020 | This alteration is classified as likely 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 14, 2016 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 26, 2021 | The BRCA1 c.1534C>T (p.Leu512Phe) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41246014-G-A). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however in vitro functional studies have shown that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (BS3; PMID: 32546644). This variant has been reported in an individual with uterine serous carcinoma (PMID: 22811390) and an individual in a family with two or more cases of breast cancer diagnosed after 50 years of age (PMID: 11802209). In addition, this variant has been reported in three women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/17-41246014-G-A). This variant has been reported to co-occur with pathogenic variants in BRCA1 and BRCA2 (BP2; UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: PP3, BS3, BS2_supporting, BP2. - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Leu512Phe variant was identified in 4 of 2744 proband chromosomes (frequency: 0.001) from German, American and British individuals or families with HBOC or endometrial cancer (Meindl_2002_11802209, Pennington_2012_22811390, Plaskocinska_2016_27208206). The variant was also identified in dbSNP (ID: rs41286294) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by GeneDx, Invitae and SCRP; and uncertain significance by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Quest Diagnostics Nichols Institute San Juan Capistrano, Counsyl and BIC ), Clinvitae (5x), Genesight-COGR (1x), LOVD 3.0 (1x ), UMD-LSDB (9x as class 2 - likely neutral, co-occurring with pathogenic BRCA2 variants (c.8023A>G, p.Ile2675Val and c.5909C>A, p.Ser1970X)), and BIC Database (6x with unknown clinical importance, classification pending); and was not identified in Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276590 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 11 of 126252 chromosomes (freq: 0.00009), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Leu512Phe residue is 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
BRCA1-related cancer predisposition Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 06, 2024 | - - |
BRCA1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 02, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;.;D;.
Polyphen
D;.;.;P;.;.;.
Vest4
MVP
MPC
0.46
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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