chr17-43047699-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1BP6_Very_Strong
The ENST00000468300.5(BRCA1):c.2025T>A(p.Cys675Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,188 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. C675C) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000468300.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.5411T>A | p.Val1804Asp | missense_variant | 22/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5411T>A | p.Val1804Asp | missense_variant | 22/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251482Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135912
GnomAD4 exome AF: 0.0000616 AC: 90AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727244
GnomAD4 genome AF: 0.000204 AC: 31AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74474
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:3Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
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 = 0.0000374 - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 01, 2011 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2020 | This variant is associated with the following publications: (PMID: 24916970, 21990134, 12014998, 28758972, 17924331, 24728327, 15350310, 17308087, 15172985, 12955716, 16528612, 19770520, 20516115, 22753008, 14534301, 17305420, 21447777, 22505045, 21520273, 25637381, 25782689, 23867111, 27272900, 26764160, 26332594, 28781887, 30209399, 30765603, 26689913) - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | BRCA1: BP1 - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:3
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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 02, 2015 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
Likely benign, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2020 | The p.Cys675X variant in BRCA1 is classified as likely benign because it has been identified in 0.048% (5/10370) of Ashkenazi Jewish and 0.047% (17/35440) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, variant is present as nonsense variant in 1 of 6 transcripts (not major transcript), while resulting in a missense variant in the remaining 5 transcripts. This variant was classified as Benign on August 10, 2015 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 55568). ACMG/AMP Criteria applied: BS1. - |
Ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Val1804Asp variant was identified in 2 of 1268 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Diez 2003), and was also identified in 2 of 2108 control chromosomes (frequency 0.001) from another study (Osorio 2007). This variant was reported in dbSNP (rs80356920) “with untested allele”, in LOVD, and in BIC 14X with unknown clinical importance. The p.Val1804Asp variant was also identified in UMD 6X as a neutral variant, where it was reported to have co-occurred with two different known BRCA1 pathogenic mutations (BRCA1 c.5266dup (p.Gln1756ProfsX74); BRCA1 c.2269delG (p.Val757PhefsX8)), increasing the likelihood that it is benign. The results of functional studies in the literature are somewhat conflicting, though most lean toward neutrality. Ostrow (2004) determined that the variant reduced transcriptional activity in a yeast-based assay, suggesting it may be deleterious; Carvalho (2007) found transcription activity comparable to wild type in yeast but reduced in mammalian cells, suggesting that it may represent a moderate-risk variant; while Lee (2010) found no functional impact of the variant on transcription. Two studies determined that the variant had no impact on protease sensitivity, and no destabilizing effect on the BRCT domain), suggesting that it is neutral (Lee 2010 20516115, Williams 2003 14534301. In addition, histopathology results provide evidence for neutrality, with loss of the variant allele in tumour tissue (Spearman 2008 18824701). Furthermore, the p.Val1804 residue is poorly conserved in mammals and lower organisms; computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; and in silico structural or probability-based models suggest that this is a neutral variant (Capanu 2011, Easton 2007, Lindor 2012, Mirkovic 2004). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at