rs28897675
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.736T>G(p.Leu246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,613,334 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 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00075 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: -0.456
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=0.09997624).
BP6
Variant 17-43094795-A-C is Benign according to our data. Variant chr17-43094795-A-C is described in ClinVar as [Benign]. Clinvar id is 41835.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094795-A-C is described in Lovd as [Benign]. Variant chr17-43094795-A-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.736T>G | p.Leu246Val | 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.736T>G | p.Leu246Val | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.000269 AC: 41AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000308 AC: 77AN: 249978Hom.: 0 AF XY: 0.000296 AC XY: 40AN XY: 135204
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GnomAD4 exome AF: 0.000753 AC: 1100AN: 1461064Hom.: 0 Cov.: 33 AF XY: 0.000669 AC XY: 486AN XY: 726878
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GnomAD4 genome 0.000269 AC: 41AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74462
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ClinVar
Significance: Benign
Submissions summary: Uncertain:7Benign:28
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:7
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Jun 08, 2014 | - - |
| 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 = 0.000000531 - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jun 04, 2015 | - - |
not specified Uncertain:1Benign:7
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 15, 2016 | - - |
| Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | 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: This variant has been reported in HGMD in 1 individual, showing that it leads to loss of expression of BRCA1. This variant is present in ExAC with a Max MAF of 0.04% (25/65600 chrs). It is classified in ClinVar with 3 stars as benign by 5 submitters (including expert panel ENIGMA), Likely benign by 3 submitters, and VUS by 3 submitters. - |
not provided Uncertain:1Benign:4
| Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 31, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2018 | This variant is associated with the following publications: (PMID: 27153395, 22703879, 24055113, 19200354, 23867111, 21520273, 25637381, 21990134, 25782689, 15235020, 16014699, 21965345, 15307796, 15300854, 25823446, 26246475, 26332594, 33087888) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | BRCA1: BP1, BS3:Supporting - |
| Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 03, 2017 | - - |
Breast and/or ovarian cancer Uncertain:2Benign:2
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 15, 2022 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 07, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Mar 15, 2002 | - - |
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 15, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Oct 25, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 13, 2015 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 25, 2016 | - - |
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
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 22, 2022 | - - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1, p.Leu246Val variant was identified in 7 of 7716 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Akbari 2011, Capanu 2011, Diez 2003). The variant was also identified in dbSNP (ID: rs28897675) “With Uncertain significance allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a benign variant by the Invitae, GeneDx and Ambry genetics; classified as Likely benign by Counsyl; classified as Uncertain significance by BIC, by Biesecker Laboratory and by CSER_CC_NCGL), GeneInsight COGR database (1X, classified as “Benign” by a clinical laboratory), the BIC database (80X with unknown clinical importance), and UMD (17X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 c.3901_3902delAG (p.Ser1301X); BRCA2 c.5984dup (p.Asn1995delinsLys)), increasing the likelihood that the p.Leu246Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), Exome Variant Server project in 3 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 26 of 76950 chromosomes (frequency: 0.0003) from a population of European (Non-Finnish) and Latino individuals, increasing the likelihood this could be a low frequency benign variant. The p.Leu246 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, the Val residue is also present in opossum, which would increase the likelihood this variant may not have functional significance. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. RNA based analysis by Sharp (2004) suggest that the mutation is associated with either constitutive skipping of exon 11, or monoallelic BRCA1 expression. However, two functional studies characterized the variant as neutral (Abkevich 2004, Gómez García 2009). In addition, this variant have been observed with two or more known deleterious mutations, increasing the likelihood this variant does not have clinical significance (Tavtigian 2006, Judkins 2005). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;T;.;T;.;T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;M;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;N;.;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;D;T;D;D;T;D;T;T;.;T;T;T
Sift4G
Benign
T;T;T;T;T;.;.;T;.;T;.;T;.;T
Polyphen
D;.;.;.;D;.;D;.;.;P;.;.;.;.
Vest4
MVP
MPC
0.45
ClinPred
T
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