rs80356874
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.2669G>T(p.Gly890Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. G890R) 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 -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2669G>T | p.Gly890Val | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2669G>T | p.Gly890Val | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251020Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135654
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461684Hom.: 0 Cov.: 51 AF XY: 0.0000303 AC XY: 22AN XY: 727132
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74244
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 03, 2008 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
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 = 0.00000408 - |
Benign, criteria provided, single submitter | clinical testing | Counsyl | Apr 14, 2016 | - - |
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 25, 2022 | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 12, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 13, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2021 | This variant is associated with the following publications: (PMID: 22753008, 16267036, 11606101, 16683254, 21990134, 17924331, 12531920, 15235020) - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 07, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 24, 2016 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
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.Gly890Val variant was identified in 2 of 9848 proband chromosomes (frequency: 0.0002) from individuals or families with hereditary breast and ovarian cancer (Schorge 2001, van der Hout 2006). The variant was identified in dbSNP (rs80356874) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, Sinai Health System, BIC and SCRP, likely benign by Ambry Genetics, GeneDx, ARUP and Mayo Clinic and benign by ENIGMA, Counsyl and Color) and LOVD 3.0 (observed 5x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 5 of 251,020 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 16,254 chromosomes (freq: 0.0001), European in 3 of 113,454 chromosomes (freq: 0.00003), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Gly890Val 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. The variant occurs outside of the splicing consensus sequence and 2 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2023 | Variant summary: BRCA1 c.2669G>T (p.Gly890Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251020 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2669G>T, has been reported in affected individuals via publications with no co-segregation information to rule in or rule out causation. In particular, the variant has been reported (Schorge_2001) in one family to be present in an unaffected individual. No details about the nature or extent of family member testing (i.e., co-segregation) were provided. Authors called this variant as a polymorphism. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007 and Lindor_2012). Eleven submitters (including an expert panel-ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at