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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L512V) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.1534C>T | p.Leu512Phe | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.1534C>T | p.Leu512Phe | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250832Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135590
GnomAD4 exome AF: 0.000123 AC: 180AN: 1461684Hom.: 0 Cov.: 34 AF XY: 0.0000990 AC XY: 72AN XY: 727118
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74316
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:3
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 23, 2003 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 05, 2012 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
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 - |
not specified Benign:4
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 | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
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. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 04, 2020 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2023 | - - |
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 | Invitae | 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 condition Benign:1
Likely benign, criteria provided, single submitter | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at