rs80357084
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6
The NM_007294.4(BRCA1):c.154C>T(p.Leu52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,600,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L52H) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.154C>T | p.Leu52Phe | missense_variant | 4/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.154C>T | p.Leu52Phe | missense_variant | 4/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000998 AC: 25AN: 250602Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135554
GnomAD4 exome AF: 0.0000704 AC: 102AN: 1448890Hom.: 1 Cov.: 28 AF XY: 0.0000652 AC XY: 47AN XY: 721410
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:6Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Leu52Phe variant has been identified in 11 out of 3896 proband chromosomes (frequency 0.003) from individuals with breast and ovarian cancers, and was not identified in 668 control chromosomes (Kim 2006, Han 2006, Sugano 2008 ), increasing the likelihood this variant may have clinical significance. However, it should be noted that this individual was indicated as Asian, and our lab has sequenced the BRCA1 gene in a limited number of individuals from this background such that the full spectrum of benign variation may not yet been defined for this gene in this population and increasing the possibility that this may be a benign variant. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357084) with no frequency information available, and so the frequency of this variant in the general population is not known. The p.Leu52 is conserved in mammals and other species and in-silico or computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that this variant may impact protein function, however this is not predictive enough to assume pathogenicity. Several in vitro studies suggested modest to no effect regarding the role of this variant in centrosome duplication, binding to BARD1, and ubiquitination activity (Brzovic 2003, Morris 2006, Ransburgh 2010, Sarkar 2008, Katoh 2005, Kais 2012, Atipairin 2011). In summary, based on current information presented above, we cannot rule out the possibility that this variant may have clinical significance, but this variant is classified as VUS. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 11, 2012 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2021 | Variant summary: BRCA1 c.154C>T (p.Leu52Phe) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 299432 control chromosomes, predominantly at a frequency of 0.0014 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.154C>T has been reported in the literature predominantly from East Asian cohorts of individuals affected with Breast and/or Ovarian Cancer (example, Sugano_2008, Han_2006, Jang_2012, Kim_2006, Judkins_2005, Eoh_2017, Yoon_2016, Park_2017, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5645C>A , p.Ser1882X), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein expression, HDR activity, or BARD1 binding (example, Yoon_2017, Starita_2015, Ransburgh_2010, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of any evidence supporting an actionable outcome spanning at-least 12 years of cross sectional review, supported by multiple reports of a neutral functional impact and at-least one co-occurrence as outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 05, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2021 | 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 | curation | Sema4, Sema4 | Dec 02, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2022 | Observed in individuals with personal history of breast and/or ovarian cancer, but also in healthy controls (Han 2006, Kim 2006, Sugano 2008, Jang 2012, Hirotsu 2015, Nakamura 2015, Yoon 2017, Hwang 2017, Ryu 2017, Choi 2018, Li 2019, Kim 2020, Momozawa 2021); Published functional studies are conflicting: BARD1 binding, single-stranded DNA repair activity, and cell survival similar to wild-type, mixed results with respect to homology-directed repair and E3 ubiquitin ligase activity, decreased E2 binding, and intermediate increase in centrosome amplification (Brzovic 2003, Morris 2006, Ransburgh 2010, Kais 2012, Towler 2013, Starita 2015, Findlay 2018, Starita 2018, Kweon 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 273C>T; This variant is associated with the following publications: (PMID: 23161852, 17100994, 20967475, 22217648, 26709275, 28111427, 32803532, 21725363, 12732733, 20103620, 19016756, 16949048, 25802882, 27658390, 24249303, 18528753, 25823446, 28392550, 28364669, 21309043, 11573085, 28440963, 25186627, 15385441, 16267036, 29020732, 29215753, 18493658, 28970858, 29176636, 29731985, 30209399, 30415210, 30725392, 31131967, 30866919, 29240602, 31467430, 29752822, 32548945, 31924417, 32973888, 31907386, 32741062, 32377563, 33606355, Paquette[article]2021, 24389207, 20104584, 8944023, 33720123, 32467295, 30287823, 33428613, 33875706, 30219179, 35373174, 16403807) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 04, 2022 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Breast Center, Key Laboratory of Carcinogenesis and Translational Research | May 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 23, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at