rs55914168
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The ENST00000357654.9(BRCA1):c.2351C>T(p.Ser784Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,816 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S784A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000357654.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2351C>T | p.Ser784Leu | 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.2351C>T | p.Ser784Leu | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000176 AC: 44AN: 250640Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135436
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461586Hom.: 0 Cov.: 41 AF XY: 0.0000468 AC XY: 34AN XY: 727078
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74420
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
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 = 0.000071 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 28, 2009 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 29, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 15, 2019 | 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. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 25, 2020 | Variant summary: BRCA1 c.2351C>T (p.Ser784Leu) 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. These in silico predictions have not been verified with functional studies, with one study classifying the variant as benign, based on a homozygous occurrence in a patient derived LCL sample, and therefore using it as a control in the study (Loke_2015). The variant allele was found at a frequency of 0.00018 in 250640 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.2351C>T, has been reported in the literature in individuals affected with tumors that belong to the HBOC spectrum, but without strong evidence for causality (e.g. Judkins_2005, McKean-Cowdin_2005, van der Hout_2006, Li_2018, Shao_2019, Abe_2019), moreover, in some of these studies, it was also found in healthy controls (McKean-Cowdin_2005, Li_2018). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.942_956delinsCTTACTTC (p.Arg1315fsX24) and RB1 c.1411C>T (p.Gln471X), in two internal LCA samples), providing supporting evidence for a benign role. In addition, a recent multifactorial likelihood analysis predicted this variant to be Benign (Parsons_2019). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x), likely benign (3x), or benign (2x; including the expert panel). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2020 | This variant is associated with the following publications: (PMID: 16683254, 16267036, 16518693, 12531920, 15726418, 15001988, 25782689, 25652403, 25348012, 15385441) - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 20, 2023 | - - |
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.Ser784Leu variant was identified in 3 of 4154 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary breast and ovarian cancer and was present in 18 of 11,404 control chromosomes (frequency: 0.001) from healthy individuals (McKean-Cowdin 2005,van der Hout 2006, Li 2018, Fernandez-Lopez 2019). The variant was identified in dbSNP (rs55914168) as “with likely pathogenic, other allele”, ClinVar (classified as likely benign by Ambry Genetics, Invitae, Color and 2 other submitters and uncertain significance by GeneDx, Counsyl and 3 other submitters), LOVD 3.0 (observed 15x), UMD-LSDB (observed 2x). The variant was identified in control databases in 45 of 282,304 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 43 of 33,396 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24,966 chromosomes (freq: 0.00004), European in 1 of 128,600 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser784 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 26, 2024 | 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). - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at