17-43099786-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1
The NM_007294.4(BRCA1):c.536A>G(p.Tyr179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,608,112 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y179F) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.536A>G | p.Tyr179Cys | missense_variant | 7/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.536A>G | p.Tyr179Cys | missense_variant | 7/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000348 AC: 53AN: 152216Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.000258 AC: 65AN: 251464Hom.: 0 AF XY: 0.000338 AC XY: 46AN XY: 135898
GnomAD4 exome AF: 0.000336 AC: 489AN: 1455778Hom.: 7 Cov.: 30 AF XY: 0.000353 AC XY: 256AN XY: 724678
GnomAD4 genome ? AF: 0.000348 AC: 53AN: 152334Hom.: 1 Cov.: 31 AF XY: 0.000403 AC XY: 30AN XY: 74490
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:12
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 = 0.00000000000173 - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 19, 2018 | 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Apr 07, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2015 | - - |
not specified Benign:10
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 04, 2015 | - - |
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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 19, 2022 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 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: ClinVar: 6 B/LB, including expert panel - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 18, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | BRCA1: BP1, BS3:Moderate, BS1 - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 01, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 03, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 15, 2014 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 05, 2018 | - - |
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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 25, 2020 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 07, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 02, 2015 | - - |
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 | Feb 22, 2023 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Tyr179Cys variant has been identified in 11 of 5342 proband chromosomes (frequency 0.002) in individuals with breast or ovarian cancers (Akbari 2011, Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012, Russo 2007, Solano 2012) and was absent in 400 control chromosomes from these studies. Myriad reports this variant as a polymorphism, and Exome Server Project reports a frequency of 0.0003 in European American alleles, and 0.0002 in African American alleles. This variant has been also been reported in dbSNP (ID: rs56187033) “with non-pathogenic allele”, in the BIC database 54X as a variant of unknown clinical importance, and in UMD 27X as a neutral variant which co-occurred with pathogenic mutations in BRCA1 or BRCA2 four times (BRCA1 c.2043dup (p.Asn682X), BRCA1 c.191G>A (p.Cys64Tyr), BRCA2 c.6082_6086delGAAGA (p.Glu2028LysfsX19), BRCA2 c.5909C>A (p.Ser1970X)). The p.Tyr179 residue is conserved in mammals; however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and this information is not very predictive of pathogenicity. Functional studies on the p.Tyr179Cys variant have suggested that it may have a deleterious effect on BRCA1 function, in assays evaluating its effect in homologous repair (Caligo 2008, Di Cecco 2009), non-homologous end-joining (Guidugli 2011), interaction of BRCA1 with Filamin A (Velkova 2010), and accumulation of BRCA1 at double-strand breaks (Wei 2008). Many studies have identified the p.Tyr179Cys variant co-occurring with two other BRCA1 variants, p.Phe486Lys and p.Asn550His, in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012), suggesting that together they constitute a rare haplotype (Tavtigian 2006). Furthermore, Augello (2006) identified these three mutations in three members of one family indicating that they exist in cis, and suggests that the presence of the three variants might produce an effect on the conformation of the protein and, consequently, on its function. In summary, this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at